was read the article
array:24 [ "pii" => "S2387020618302195" "issn" => "23870206" "doi" => "10.1016/j.medcle.2018.05.027" "estado" => "S300" "fechaPublicacion" => "2018-07-23" "aid" => "4397" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2018" "documento" => "article" "crossmark" => 1 "subdocumento" => "pgl" "cita" => "Med Clin. 2018;151:80.e1-80.e10" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S0025775318300356" "issn" => "00257753" "doi" => "10.1016/j.medcli.2017.12.010" "estado" => "S300" "fechaPublicacion" => "2018-07-23" "aid" => "4397" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "pgl" "cita" => "Med Clin. 2018;151:80.e1-80.e10" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 34 "formatos" => array:2 [ "HTML" => 22 "PDF" => 12 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Conferencia de consenso</span>" "titulo" => "Documento de consenso sobre la implementación de la secuenciación masiva de nueva generación en el diagnóstico genético de la predisposición hereditaria al cáncer" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "80.e1" "paginaFinal" => "80.e10" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Consensus document on the implementation of next generation sequencing in the genetic diagnosis of hereditary cancer" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José Luis Soto, Ignacio Blanco, Orland Díez, Javier García Planells, Isabel Lorda, Gert Matthijs, Mercedes Robledo, Erika Souche, Conxi Lázaro" "autores" => array:9 [ 0 => array:2 [ "nombre" => "José Luis" "apellidos" => "Soto" ] 1 => array:2 [ "nombre" => "Ignacio" "apellidos" => "Blanco" ] 2 => array:2 [ "nombre" => "Orland" "apellidos" => "Díez" ] 3 => array:2 [ "nombre" => "Javier" "apellidos" => "García Planells" ] 4 => array:2 [ "nombre" => "Isabel" "apellidos" => "Lorda" ] 5 => array:2 [ "nombre" => "Gert" "apellidos" => "Matthijs" ] 6 => array:2 [ "nombre" => "Mercedes" "apellidos" => "Robledo" ] 7 => array:2 [ "nombre" => "Erika" "apellidos" => "Souche" ] 8 => array:2 [ "nombre" => "Conxi" "apellidos" => "Lázaro" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020618302195" "doi" => "10.1016/j.medcle.2018.05.027" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020618302195?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775318300356?idApp=UINPBA00004N" "url" => "/00257753/0000015100000002/v1_201807060854/S0025775318300356/v1_201807060854/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020618302110" "issn" => "23870206" "doi" => "10.1016/j.medcle.2018.05.019" "estado" => "S300" "fechaPublicacion" => "2018-07-23" "aid" => "4297" "copyright" => "Elsevier España, S.L.U." "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2018;151:81-2" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2 "PDF" => 2 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Maxillar osteonecrosis associated to denosumab in a patient with systemic mastocytosis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "81" "paginaFinal" => "82" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Osteonecrosis maxilar asociada a tratamiento con denosumab en una paciente con mastocitosis sistémica" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 972 "Ancho" => 750 "Tamanyo" => 36333 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Area of osteonecrosis and osteolysis in the left jaw with bone sequestrum (the arrow represents the lesion).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José Darío Sánchez López, Paolo Cariati, Miguel Pérez de Perceval Tara" "autores" => array:3 [ 0 => array:2 [ "nombre" => "José Darío" "apellidos" => "Sánchez López" ] 1 => array:2 [ "nombre" => "Paolo" "apellidos" => "Cariati" ] 2 => array:2 [ "nombre" => "Miguel" "apellidos" => "Pérez de Perceval Tara" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775317307881" "doi" => "10.1016/j.medcli.2017.10.010" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775317307881?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020618302110?idApp=UINPBA00004N" "url" => "/23870206/0000015100000002/v1_201807220502/S2387020618302110/v1_201807220502/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020618302122" "issn" => "23870206" "doi" => "10.1016/j.medcle.2018.05.020" "estado" => "S300" "fechaPublicacion" => "2018-07-23" "aid" => "4305" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2018;151:71-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Encephalitis associated with antibodies against the NMDA receptor" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "71" "paginaFinal" => "79" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Encefalitis por anticuerpos contra el receptor de NMDA" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified by Armangue et al.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">50</span></a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2237 "Ancho" => 3000 "Tamanyo" => 327002 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Drawings made by a patient with autoimmune post–herpes simplex encephalitis, comparing the initial phase of the disease with the post-immunotherapy phase. An example is shown by drawings made by a 56-year-old female patient with autoimmune post–herpes simplex encephalitis at the time of symptoms onset (tree, family and home: A, D and G), 3 weeks after immunotherapy (B, E, H) and at 6 months of follow-up (C, F and <span class="elsevierStyleSmallCaps">I</span>). At the onset of the disease, the patient had severe anterograde amnesia, disorientation, confusion and disorganized thinking. After treatment, the patient improved, and most symptoms resolved, except for amnesia and temporary disorientation.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Mar Guasp, Josep Dalmau" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Mar" "apellidos" => "Guasp" ] 1 => array:2 [ "nombre" => "Josep" "apellidos" => "Dalmau" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775317307972" "doi" => "10.1016/j.medcli.2017.10.015" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775317307972?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020618302122?idApp=UINPBA00004N" "url" => "/23870206/0000015100000002/v1_201807220502/S2387020618302122/v1_201807220502/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Consensus statement</span>" "titulo" => "Consensus document on the implementation of next generation sequencing in the genetic diagnosis of hereditary cancer" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "80.e1" "paginaFinal" => "80.e10" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "José Luis Soto, Ignacio Blanco, Orland Díez, Javier García Planells, Isabel Lorda, Gert Matthijs, Mercedes Robledo, Erika Souche, Conxi Lázaro" "autores" => array:9 [ 0 => array:3 [ "nombre" => "José Luis" "apellidos" => "Soto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Ignacio" "apellidos" => "Blanco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Orland" "apellidos" => "Díez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Javier" "apellidos" => "García Planells" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "Isabel" "apellidos" => "Lorda" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] 5 => array:3 [ "nombre" => "Gert" "apellidos" => "Matthijs" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "aff0035" ] ] ] 6 => array:3 [ "nombre" => "Mercedes" "apellidos" => "Robledo" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">h</span>" "identificador" => "aff0040" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] 7 => array:3 [ "nombre" => "Erika" "apellidos" => "Souche" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "aff0035" ] ] ] 8 => array:4 [ "nombre" => "Conxi" "apellidos" => "Lázaro" "email" => array:1 [ 0 => "clazaro@iconcologia.net" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">i</span>" "identificador" => "aff0045" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:9 [ 0 => array:3 [ "entidad" => "Molecular Genetics Laboratory, Elche University General Hospital, Alicante Institute for Health and Biomedical Research, Alicante, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Clinical Genetics and Genetic Counseling Program, Germans Trias i Pujol Hospital, Can Ruti Campus, Badalona, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Area of Clinical and Molecular Genetics, University Hospital Vall d’Hebron, and Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Instituto de Medicina Genómica, Paterna, Valencia, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz (IIS-FJD), Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Center for Human Genetics, KU Leuven, Gasthuisberg, Laboratory for Molecular Diagnosis, on behalf of the EuroGentest/ESHG Working Group on Diagnostic NGS, Leuven, Belgium" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Documento de consenso sobre la implementación de la secuenciación masiva de nueva generación en el diagnóstico genético de la predisposición hereditaria al cáncer" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Between 5% and 10% of all cancers have a high-penetrance hereditary component as a consequence of germline mutations in genes responsible for hereditary predisposition syndromes. The genetic diagnosis of these syndromes offers the opportunity to establish effective predictive measures in patients and their families that result in a decrease in cancer morbidity and mortality in families with a high genetic risk.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In Spain, genetic studies carried out in the context of hereditary cancer are covered by the Biomedical Research Law 14/2007 of July 3. This law establishes that any diagnostic genetic analysis must be done by medical prescription and, before carrying it out, the patients or individuals to study must receive a pretest genetic counselling that includes adequate information about the suspected syndrome, what the genetic study involves, what are the possible expected results and their meaning. After being duly informed, they must sign their consent so that they can proceed with the genetic study. These studies must be carried out by qualified professionals in duly authorized laboratories and accredited by the competent authorities. The patient must be informed of the results in the context of a post-test genetic counselling.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Genetic diagnostic techniques applied to the field of hereditary cancer focus on the analysis of germline genetic alterations (point mutations and large rearrangements) in those genes responsible for the suspected syndromes.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The technology used for about 25 years and still considered the <span class="elsevierStyleItalic">gold standard</span> today is the Sanger sequencing. The development of mass sequencing or new generation techniques (<span class="elsevierStyleItalic">next generation sequencing</span> [NGS]) represents, in general terms, an important turning point in genetic diagnosis. NGS allows rapid sequencing of billions of base pairs of DNA from an individual. The rapid development and great success of these technologies in research herald a new era in genetic diagnosis. This technology offers a significant improvement in efficiency, allowing an increase in the performance of the analysis with a substantial reduction in response time and economic costs. The great capacity of analysis of these new systems makes possible the simultaneous study of large panels of genes, exomes and even complete genomes.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The new technologies pose new challenges, both at the technical level and in the handling of data, in the interpretation of results and in genetic counselling. For the implementation of NGS in care diagnosis, many important aspects must be considered, and this is precisely the purpose of this document.</p><p id="par0030" class="elsevierStylePara elsevierViewall">These guidelines have been prepared by the Spanish Association of Human Genetics (AEGH), the Spanish Society of Laboratory Medicine (SEQC-ML) and the Spanish Society of Medical Oncology (SEOM).</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Scope and objective</span><p id="par0035" class="elsevierStylePara elsevierViewall">The present guidelines are aimed at the genetic diagnosis of syndromes of hereditary cancer predisposition through NGS technology, either through the study of gene panels, either through the specific capture of these genes, or by extracting the results of the genes of interest from the analysis of complete exomes.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Although a large part of the recommendations included in this document may have a more general application and be useful for any monogenic congenital disease, some of the approaches or recommendations presented here may be valid only for hereditary cancer and may not be extrapolated to other congenital monogenic diseases because they require a more specific management.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The objective of these guidelines is to establish a framework of useful recommendations for a planned and controlled implementation of NGS in the context of hereditary cancer predisposition, enhancing the strengths and opportunities offered by this technology and minimizing the weaknesses and threats that may be derived from its use.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Methodology</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Method of preparation, revision, approval and update of the guidelines</span><p id="par0050" class="elsevierStylePara elsevierViewall">The initial proposal for the preparation of this document originated from the Hereditary Cancer Committee of the AEGH, which was presented to the board of directors of said society. The proposal was approved and the Hereditary Cancer Committee liaison person of the board of directors and the president of said committee were appointed as document preparation coordinators. It was agreed to form an operating group with a small number of experts for the preparation of a first draft. Professionals from the laboratory and clinical areas are represented in this group (authors who signed the document), as well as from the professional societies that are most directly interested, namely AEGH, SEQC-ML and SEOM. The coordinators explained the objectives of the document to the group of experts. The available international guidelines were reviewed<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">1–6</span></a> and a literature review was made using indexed bibliography search tools (PubMed) for each of the sections to be considered. It was agreed to prepare the guidelines mainly based on the recommendations of the <span class="elsevierStyleItalic">European Society of Human Genetics</span> (ESHG),<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> adapting it to our environment and considering any relevant current organizational and bio-legal aspects. Our colleagues, the authors of the European guidelines of the ESHG, were informed of this project, welcomed the initiative and agreed to collaborate. Several meetings were held by teleconference of the whole group in the initial design and organization phase and in the final document editing phase. Throughout the process, there was a smooth communication by email. All the information, documents and references of interest were stored on a virtual hard disk to which the entire group had access. The final recommendations were reviewed, discussed and agreed upon by the group of experts. The first draft was distributed to the boards of the Hereditary Cancer Section of the SEOM, the Genetics Committee of the SEQC-ML and the Hereditary Cancer Committee of the AEGH, as external reviewers, for their evaluation. After including the considerations and suggestions received, the document was accepted by the 3 societies.</p><p id="par0055" class="elsevierStylePara elsevierViewall">After the final editing of the consensus document, the document was sent to 3 external experts, according to the AGREE protocol II as a tool that assesses methodological accuracy and transparency with which the guidelines have been prepared (<a id="intr0015" class="elsevierStyleInterRef" href="http://www.agreetrust.org/">http://www.agreetrust.org</a>).<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a> The 3 experts evaluated the guidelines and sent their observations to the coordinators. Finally, the final document was reviewed again by the working group and sent to the experts for final acceptance. The methodology of the external evaluation, and the results of this, are detailed in Appendix A (Supplementary material 1), available on the web. The societies AEGH, SEOM and SEQCC-ML will oversee disseminating the published guidelines to all its partners and sector professionals. Likewise, the document will be accessible on the web pages of the respective societies.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Population and professionals to whom the guidelines are addressed</span><p id="par0060" class="elsevierStylePara elsevierViewall">These guidelines are intended to be a useful tool for health professionals involved in the process of genetic diagnosis of patients with suspected inherited predisposition to cancer syndromes using NGS technology (mainly molecular and clinical geneticists and genetic counsellors in hereditary cancer).</p><p id="par0065" class="elsevierStylePara elsevierViewall">This tool projects its service towards a greater genetic diagnosis performance, ensuring a reasonable use of NGS technology and the quality levels required in diagnostic procedures. Consequently, these guidelines have a direct impact on patients and families with inherited cancer syndromes. Overall, it is considered that between 5% and 10% of all cancers have a hereditary component of high-penetrance. Considering the cancer incidence prediction in Spain for the year 2015 – about 227,076 cases<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> – it would mean that between 11,353 and 22,707 of these new cases could have a hereditary origin.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The vast majority of these syndromes are considered rare diseases (affecting less than 5 out of every 10,000 inhabitants), although syndromes such as hereditary breast and ovarian or Lynch syndrome have a much higher incidence. These syndromes are becoming the paradigm of predictive, preventive and personalized medicine or precision medicine.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Detailed information on hereditary cancer predisposition syndromes that can be diagnosed genetically can be found in GeneReviews (<a id="intr0020" class="elsevierStyleInterRef" href="https://www.ncbi.nlm.nih.gov/books/NBK1116/">https://www.ncbi.nlm.nih.gov/books/NBK1116/</a>),<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> Orphanet (<a id="intr0025" class="elsevierStyleInterRef" href="http://www.orpha.net/consor/cgi-bin/Disease.php?lng=ES">http://www.orpha.net/consor/cgi-bin/Disease.php?lng=ES</a>)<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> and Lindor et al., 2008.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Review and update of the guidelines</span><p id="par0080" class="elsevierStylePara elsevierViewall">The planned systematic update of the guidelines implies an annual review since their publication and, if considered necessary, their update. In this case, the working group will address the update with the same methodology followed in the preparation of the original document, including the external review by committees/sections related to hereditary cancer of professional societies.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Structure of the guidelines and levels of evidence</span><p id="par0085" class="elsevierStylePara elsevierViewall">Although the use of NGS in genetic diagnosis in general, and in hereditary cancer in particular, is supported by a considerable and growing level of scientific evidence, for its correct implementation it is necessary to take into account a series of aspects, both bioethical and organizational as well as technical and advisory, in order to minimize and control the inherent limitations of this novel technological system. Limitations, such as aspects related to analytical quality, interpretation of genetic variants or incidental findings.</p><p id="par0090" class="elsevierStylePara elsevierViewall">There is a good number of studies, both retrospective and prospective, which show that the use of NGS provides a greater diagnostic yield in hereditary cancer with more savings in terms of economic costs and time compared to those offered by the Sanger technique, considered as the <span class="elsevierStyleItalic">gold standard</span>.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">12–14</span></a> Using the classification proposed by the Oxford Centre for Evidence-Based Medicine for aspects related to diagnosis (<a id="intr0030" class="elsevierStyleInterRef" href="http://www.cebm.net/index.aspx?o=5653">http://www.cebm.net/index.aspx?o=5653</a>),<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</span></a> we can state that we have a grade of recommendation A, level of evidence 1c. That is, these are diagnostic tests with such high specificity that a positive result confirms the diagnosis, and with sensitivity so high that a negative result can rule out the diagnosis.</p><p id="par0095" class="elsevierStylePara elsevierViewall">In this consensus document, a total of 41 statements grouped into 6 sections are provided:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">(1)</span><p id="par0100" class="elsevierStylePara elsevierViewall">Clinical and diagnostic utility.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">(2)</span><p id="par0105" class="elsevierStylePara elsevierViewall">Informed consent and pretest and post-test genetic counselling.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">(3)</span><p id="par0110" class="elsevierStylePara elsevierViewall">Validation of analytical procedures.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">(4)</span><p id="par0115" class="elsevierStylePara elsevierViewall">Results report.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">(5)</span><p id="par0120" class="elsevierStylePara elsevierViewall">Information management.</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">(6)</span><p id="par0125" class="elsevierStylePara elsevierViewall">Distinction between research and healthcare areas.</p></li></ul></p><p id="par0130" class="elsevierStylePara elsevierViewall">Most statements related to informed consent and genetic counselling generally present a level of evidence 2 and a grade of recommendation B. The sections on information management and the distinction between healthcare and research areas are difficult to assess in terms of scientific evidence measurable by the OCBM criteria, so they have been considered as the result of the recommendation of experts (level of evidence 5 and grade of recommendation D). Classification details on levels of evidence and degree of recommendation of each of the statements made in the document are detailed in Supplementary material 2 of Appendix A, available on the web.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical and diagnostic utility</span><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDisplayedQuote" id="dsq0005"><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Statement 01: <span class="elsevierStyleItalic">NGS should not be transferred to clinical practice without acceptable validation according to the guidelines. The level of accuracy and desired thoroughness in the validation must be that established by ISO 15189 or similar</span>.</p></span></p><p id="par0140" class="elsevierStylePara elsevierViewall">The development and application of new technologies in diagnosis involves a complex process with important implications and difficulties that go far beyond the complexity of the technique itself. The key elements to ensure the success of the use of a new technology in diagnosis are detailed in the ACCE framework: analytical validation, clinical validation, clinical utility and consideration of the ethical and legal implications of the test itself.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a> A documented process of validation or analytical verification is required for each test by the laboratory before its diagnostic use.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</span></a> This procedure must be recorded in a validation report in which the objective of the test, its analytical validity, including the sensitivity and specificity obtained in the validation process, and its detection limits are clearly described. The scientific evidence on the clinical validation and clinical utility of the analysis by NGS should be included in the operating procedure.<span class="elsevierStyleDisplayedQuote" id="dsq0010"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Statement 02: <span class="elsevierStyleItalic">The laboratory must specify whether the test it offers can be used to exclude or confirm a diagnosis</span>.</p></span></p><p id="par0145" class="elsevierStylePara elsevierViewall">The objective of the diagnostic study – confirmation or exclusion of a diagnostic suspicion – must be previously defined in each test. The distinction between the two objectives depends on the scope of the test and offers a different view of the diagnosis. In most cases of hereditary cancer predisposition, the diagnostic studies that are carried out aim to confirm a diagnosis of clinical suspicion when it comes to index cases.<span class="elsevierStyleDisplayedQuote" id="dsq0015"><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Statement 03: <span class="elsevierStyleItalic">The purpose and utility of the genetic study must be defined at the beginning of the validation and a summary thereof must be included in the corresponding validation report</span>.</p></span></p><p id="par0150" class="elsevierStylePara elsevierViewall">The implementation of NGS offers the opportunity of the simultaneous analysis of a large number of genes in a reduced time and with increasingly low costs, which allows, ultimately, greater efficiency and diagnostic performance. But this powerful technology also has some technical limitations that must be considered, especially in its diagnostic use, since they will substantially affect the sensitivity and specificity of the test. Some of these NGS limitations depend on several factors that affect the whole process, such as the sequencing platform, the enrichment methods of the regions of interest, the generation of libraries, the processing and bioinformatic analysis, etc. These aspects must be addressed in the initial design of the process, as well as consider possible additional complementary or confirmatory tests that may be required to reach the final objective of the diagnostic process.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The scope of this process must be defined when validating the analytical process using NGS. Currently, the scope most frequently used in our environment is the use of NGS as SNV (<span class="elsevierStyleItalic">single nucleotide variation</span>) screening method or indel (small insertions-deletions), for later confirmation using Sanger sequencing. The use of NGS as screening of large rearrangements and subsequent confirmation with alternative techniques (MLPA, RT-PCR, aCGH, etc.) is being incorporated in an increasing way. The current use of NGS as a diagnostic method, without requiring confirmation with alternative techniques, is unusual. However, a clear trend towards this end is observed.<span class="elsevierStyleDisplayedQuote" id="dsq0020"><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Statement 04: <span class="elsevierStyleItalic">The diagnostic performance should be considered as the first indicator for the introduction of NGS in diagnosis</span>.</p></span></p><p id="par0160" class="elsevierStylePara elsevierViewall">Diagnostic performance is defined as the probability of detecting genetic variants that cause the disease in a cohort of patients. From the clinical point of view, the diagnostic performance can be a good indicator of the efficiency of the test and its clinical utility. The significant phenotypic overlap between some hereditary cancer predisposition syndromes makes it advisable to use gene panels that are broad enough so as to increase the diagnostic yield, including the genes responsible for those syndromes that may be clinically related.<span class="elsevierStyleDisplayedQuote" id="dsq0025"><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Statement 05: <span class="elsevierStyleItalic">For diagnostic use, only genes with sufficient scientific evidence regarding the association between an altered genotype and the pathology should be included in the analysis</span>.</p></span></p><p id="par0165" class="elsevierStylePara elsevierViewall">Currently, in clinical practice, genetic diagnostic laboratories prefer to offer gene panels. The criteria and levels of evidence for the inclusion of a gene in these panels must be previously defined and documented. The selection criteria must be agreed by an expert multidisciplinary team. From the point of view of equal access to health resources, the genetic studies offered to the patient should be standard and as similar as possible to those available in other European countries. It would be highly recommendable to make a coordinated effort from the national health system for the homogenization, regularization and normalization of this new scenario that arises with the incorporation of NGS in the diagnosis.<span class="elsevierStyleDisplayedQuote" id="dsq0030"><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Statement 06: <span class="elsevierStyleItalic">The list of genes for a particular syndrome must be established by clinical and laboratory experts</span>.</p></span></p><p id="par0170" class="elsevierStylePara elsevierViewall">For most hereditary cancer predisposition syndromes, there are one or several known responsible genes that explain most cases with genetic diagnosis. The laboratory should establish a procedure for the review, selection and prioritization of genes based on documented evidence. The analysis of additional genes selected to increase the diagnostic yield should not compromise the diagnostic sensitivity of the main genes related to the syndrome in question. In the design of the gene panel it is also important to consider the great limitation that NGS analysis has for the genes that have pseudogenes, like <span class="elsevierStyleItalic">PMS2</span> or <span class="elsevierStyleItalic">NF1</span>. The approach of these genes requires a special strategy to ensure the quality of the result.<span class="elsevierStyleDisplayedQuote" id="dsq0035"><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Statement 07: <span class="elsevierStyleItalic">A simple grading system, based on coverage and diagnostic performance, allows the comparison of the diagnostic test offer between different laboratories</span>.</p></span></p><p id="par0175" class="elsevierStylePara elsevierViewall">Most of the systems used for capture and enrichment of the genomic regions of interest do not have 100% efficiency. The percentage of a region or <span class="elsevierStyleItalic">gaps</span> that is not analyzed can vary considerably depending on different variables, such as the gene or genomic region analyzed, the enrichment system used, the average sequencing coverage, the type of library or the bioinformatic analysis procedure used.</p><p id="par0180" class="elsevierStylePara elsevierViewall">With the aim of being able to compare the different tests offered in order to choose the one that provides the best diagnostic performance, each laboratory must define a series of technical specifications for each of its tests.<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0185" class="elsevierStylePara elsevierViewall">Design (criteria and evidence).</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0190" class="elsevierStylePara elsevierViewall">Enrichment technology used and library preparation.</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0195" class="elsevierStylePara elsevierViewall">Sequencing technology.</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0200" class="elsevierStylePara elsevierViewall">Average sequencing depth (vertical coverage) (or minimum if possible).</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">-</span><p id="par0205" class="elsevierStylePara elsevierViewall">Estimated diagnostic performance for each gene or region analyzed based on the depth of sequencing used and, if possible:</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">•</span><p id="par0210" class="elsevierStylePara elsevierViewall">Percentage of each gene represented (horizontal coverage).</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">•</span><p id="par0215" class="elsevierStylePara elsevierViewall">Description of <span class="elsevierStyleItalic">gaps</span> and their management.</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">-</span><p id="par0220" class="elsevierStylePara elsevierViewall">Bioinformatic procedure used.</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">-</span><p id="par0225" class="elsevierStylePara elsevierViewall">Classification algorithm and prioritization of variants.</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">-</span><p id="par0230" class="elsevierStylePara elsevierViewall">Type of information included in the report.</p></li></ul></p><p id="par0235" class="elsevierStylePara elsevierViewall">The report must collect the actual parameters obtained for each of these characteristics.</p><p id="par0240" class="elsevierStylePara elsevierViewall">Based on these criteria, the European recommendations<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> propose a classification of NGS-based tests in 3 large groups according to the analytical scope of the study offered. Although we consider the practical application of this classification difficult, it can serve as a reference to help decision-making regarding selecting one test group or another.</p><p id="par0245" class="elsevierStylePara elsevierViewall">These groups are the following:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0250" class="elsevierStylePara elsevierViewall">Group A test: the test ensures a 100% genetic variant detection in the defined regions of interest (normally coding regions and intron–exon junctions of the included genes). For this you can use strategies based on amplicons, an optimization of enrichment systems or mixed strategies covering the known gaps or those that do not meet the quality requirements required by Sanger sequencing.</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">-</span><p id="par0255" class="elsevierStylePara elsevierViewall">Group B test: the test allows analyzing regions of interest with a reliability greater than 99% and completes some of the sequence fragments not covered with Sanger sequencing or other complementary technology.</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">-</span><p id="par0260" class="elsevierStylePara elsevierViewall">Group C test: the test provides the performance of NGS application used. The gaps are not analyzed by complementary techniques.</p></li></ul></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Informed consent and pretest and post-test genetic counselling</span><p id="par0265" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDisplayedQuote" id="dsq0040"><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Statement 08: <span class="elsevierStyleItalic">For each requested NGS study, the laboratory must provide the clinician the following: (a) the diseases targeted in the scope of the study, (b) the list of genes that are analysed, (c) the coverage of the study in the regions of interest, (d) the analytical sensitivity and specificity, (e) the type of results (types of variants) that will be reported and (f) the diseases not related to the clinical phenotype of the patient that could be caused by pathogenic variants in the analysed genes</span>.</p></span></p><p id="par0270" class="elsevierStylePara elsevierViewall">The implications of a study based on NGS depend on many factors (design, procedures, platforms, bioinformatic analysis, etc.). Therefore, it is important that the clinician requesting the study be informed in detail about the limitations and possible unforeseen results that may arise from the study.<span class="elsevierStyleDisplayedQuote" id="dsq0045"><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Statement 09: <span class="elsevierStyleItalic">Diagnostic laboratories should establish a strategy in the analysis of the results exclusively targeting the gene or panel of genes related to the indication of the study, in order to minimize the possibility of incidental findings</span>.</p></span></p><p id="par0275" class="elsevierStylePara elsevierViewall">The possibility of finding incidental findings in NGS studies with the detection of pathogenic alterations in genes unrelated to the disease under study should be properly managed.<span class="elsevierStyleDisplayedQuote" id="dsq0050"><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Statement 10: <span class="elsevierStyleItalic">Pretest counselling should provide information on the possibility of incidental findings that involve both high-penetrance mutations, not directly related to the patient's personal or family history, as well as the status of a healthy carrier of variants associated with recessive diseases</span>.</p></span></p><p id="par0280" class="elsevierStylePara elsevierViewall">The probability of incidental findings in a panel of genes depends on the genes studied. Sometimes it can be very difficult, or even impossible, to consider individually each of the genes included in a panel. In these cases, a discussion of gene groups according to the high-penetrance syndromes that will be evaluated and associated risks if deleterious genetic variants are detected is recommended. Sufficient information should be provided so that patients can understand and be aware of the possible detection of high penetrance mutations not suggested by their personal or family history (incidental findings). In addition, heterozygous mutations can be detected in genes responsible for pathologies with recessive inheritance (healthy carriers). This is important in reproductive genetic counselling.<span class="elsevierStyleDisplayedQuote" id="dsq0055"><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Statement 11: <span class="elsevierStyleItalic">The institution must have the necessary logistics to cover the needs derived from offering the right to know and not to know about incidental findings and heterozygous carrier status</span>.</p></span></p><p id="par0285" class="elsevierStylePara elsevierViewall">Before implementing a genetic study based on NGS, the clinical centre must have an established protocol for handling incidental findings, which must be approved by an ethics committee. The patient has the right to know or not to know the results of the genetic study beyond the result that prompted the initial indication of the study. In addition, the protocol must collect whether the patient should be informed about being a healthy carrier status of an alteration responsible for a recessive disease. The laboratory must be able to handle the different options offered.<span class="elsevierStyleDisplayedQuote" id="dsq0060"><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Statement 12: <span class="elsevierStyleItalic">The policy on the communication of incidental and unsolicited findings must be clear to the patient and be reflected in the informed consent</span>.</p></span></p><p id="par0290" class="elsevierStylePara elsevierViewall">Pretest genetic counselling should include adequate discussion and information about expected outcomes including potential unexpected or secondary findings. The informed consent must include if the patient wants to be informed of the results that are not directly related to the diagnostic reason (unexpected or incidental findings), as well as the results of possible re-analysis of his/her data based on scientific advances.<span class="elsevierStyleDisplayedQuote" id="dsq0065"><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Statement 13: <span class="elsevierStyleItalic">In pretest counselling, information should be provided on the possibility of findings whose clinical implications are in the process of being defined</span>.</p></span></p><p id="par0295" class="elsevierStylePara elsevierViewall">With the use of multiple gene panels, there is the possibility of identifying deleterious genetic variants in genes of less known penetrance or genes of low or moderate penetrance, whose clinical implications and follow-up protocols are not fully defined.<span class="elsevierStyleDisplayedQuote" id="dsq0070"><p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Statement 14: <span class="elsevierStyleItalic">The identification of a pathogenic variant has diverse personal and family implications and should be considered with patients in genetic counselling</span>.</p></span></p><p id="par0300" class="elsevierStylePara elsevierViewall">After the genetic study, 3 types of results can be obtained that have to be explained prior to the test: (a) the identification of a deleterious alteration responsible for the clinical condition, (b) the absence of deleterious alterations detection and (c) the identification of genetic variants of uncertain significance.</p><p id="par0305" class="elsevierStylePara elsevierViewall">If a deleterious alteration responsible for the clinical condition is identified in the genetic study, subsequent counselling should include: (a) the personal implications of the finding, which include sharing the results with the physicians responsible for the patient's healthcare and ensuring adequate clinical follow-up; (b) family implications, highlighting the importance of sharing the results of genetic and genomic tests with family members at risk so that they can benefit from this information.<span class="elsevierStyleDisplayedQuote" id="dsq0075"><p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Statement 15: <span class="elsevierStyleItalic">In the absence of detection of a causal variant or the identification of variants of uncertain significance, guidelines for the review of said result (reclassification of variants, test extension, etc.) should be established, and included in genetic counselling</span>.</p></span></p><p id="par0310" class="elsevierStylePara elsevierViewall">If the analysis has not detected any pathogenic variant or has only detected genetic variants of uncertain significance, the current limitations of the test should be discussed, and a clinical follow-up protocol based on personal and family clinical data should be established. Likewise, follow-up periods should be established to assess the possible reclassification of variants of uncertain clinical significance, or the need to extend the genetic study if new associations between the gene panel and personal or family pathologies appear. It is important to define who should be responsible for establishing such follow-up visits.<span class="elsevierStyleDisplayedQuote" id="dsq0080"><p id="spar0130" class="elsevierStyleSimplePara elsevierViewall">Statement 16: <span class="elsevierStyleItalic">It is advisable to provide the patient with written information or access to reliable web information sources</span>.</p></span></p><p id="par0315" class="elsevierStylePara elsevierViewall">A well-informed patient facilitates and improves the process of genetic counselling, ensuring greater involvement and participation. It is important, therefore, to provide the patient with access to reliable and accurate sources of information, as well as contact with patient associations that may extend support beyond healthcare coverage.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Validation of analytical procedures</span><p id="par0320" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDisplayedQuote" id="dsq0085"><p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">Statement 17: <span class="elsevierStyleItalic">All quality measurements in NGS used in diagnostic procedures must be accurately described</span>.</p></span></p><p id="par0325" class="elsevierStylePara elsevierViewall">In the field of diagnosis, only samples whose NGS result is of good quality should be analyzed. Therefore, it is essential to establish the criteria to define a high quality in the analysis of gene panels, exomes and genomes. The quality of an NGS result depends on a combination of many factors, such as the number of readings obtained in the assay, the proportion of duplicate regions and the coverage.<span class="elsevierStyleDisplayedQuote" id="dsq0090"><p id="spar0140" class="elsevierStyleSimplePara elsevierViewall">Statement 18: <span class="elsevierStyleItalic">The diagnostic laboratory should generate a structured database with the relevant quality measures in relation to (a) the analysis platform, (b) all analyses, and (c) all samples processed</span>.</p></span></p><p id="par0330" class="elsevierStylePara elsevierViewall">NGS technology requires the supervision of the specific run characteristics and analysis of the samples. It is not necessary to communicate the procedure's monitoring data in the report, but they should be used for the laboratory's continuous internal inspection and validation.<span class="elsevierStyleDisplayedQuote" id="dsq0095"><p id="spar0145" class="elsevierStyleSimplePara elsevierViewall">Statement 19: <span class="elsevierStyleItalic">Aspects related to the traceability of samples, such as the use of barcodes for identification, should be considered for the evaluation of the assay and the validation of the platform</span>.</p></span></p><p id="par0335" class="elsevierStylePara elsevierViewall">A sample traceability method must be used, since the workflows in NGS are very complex and involve multiple processing stages, both in the laboratory and during the computer analysis.<span class="elsevierStyleDisplayedQuote" id="dsq0100"><p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">Statement 20: <span class="elsevierStyleItalic">The measurement of the accuracy and precision should be part of the general validation of the platform, although its repetition is not necessary in individual tests</span>.</p></span></p><p id="par0340" class="elsevierStylePara elsevierViewall">During platform validation, the laboratory must ensure that all its devices and reagents meet the requirements of the manufacturers. During the development of the tests and data analysis, the limitations of each technology must be identified and taken into account. In the validation, a distinction must be made between aspects related to the platform and the specific test, or the data analysis procedure.<span class="elsevierStyleDisplayedQuote" id="dsq0105"><p id="spar0155" class="elsevierStyleSimplePara elsevierViewall">Statement 21: <span class="elsevierStyleItalic">The bioinformatic procedure must adapt to the technical platform used</span>.</p></span></p><p id="par0345" class="elsevierStylePara elsevierViewall">Obviously, all sequencing technologies have strengths and weaknesses, and bioinformatic tools must reflect these characteristics.<span class="elsevierStyleDisplayedQuote" id="dsq0110"><p id="spar0160" class="elsevierStyleSimplePara elsevierViewall">Statement 22: <span class="elsevierStyleItalic">The analytical sensitivity and specificity should be established separately for each type of variant during the pipeline validation</span>.</p></span></p><p id="par0350" class="elsevierStylePara elsevierViewall">During its validation, the diagnostic protocol specifications must be measured through the evaluation of analytical sensitivity and specificity. For example, algorithms optimized for SNP detection are less accurate for small insertions or deletions. The laboratory must demonstrate that it knows these peculiarities and that the protocols for the detection of variants are adequately verified.<span class="elsevierStyleDisplayedQuote" id="dsq0115"><p id="spar0165" class="elsevierStyleSimplePara elsevierViewall">Statement 23: <span class="elsevierStyleItalic">The diagnostic laboratory must validate all the steps involved in the bioinformatic procedure (public domain tools or commercial software packages) with the standard data sets each time new versions are implemented</span>.</p></span></p><p id="par0355" class="elsevierStylePara elsevierViewall">Any change in chemistry, enrichment protocols, or bioinformatic analysis requires a new validation.<span class="elsevierStyleDisplayedQuote" id="dsq0120"><p id="spar0170" class="elsevierStyleSimplePara elsevierViewall">Statement 24: <span class="elsevierStyleItalic">The diagnostic laboratory should use a structured database for all relevant variants with updated entries</span>.</p></span></p><p id="par0360" class="elsevierStylePara elsevierViewall">Each laboratory should have a database containing all the relevant variants. This provides a very useful tool to identify platform-specific artefacts, track validation results, and provide a web/server link to access specific loci databases and meta-analysis. These databases can allow subsequent entries (for example, detection of false positives, published mutations, variants that co-segregate, etc.), which speed up the diagnostic process.<span class="elsevierStyleDisplayedQuote" id="dsq0125"><p id="spar0175" class="elsevierStyleSimplePara elsevierViewall">Statement 25: <span class="elsevierStyleItalic">The diagnostic laboratory must take measures to resolve the long-term storage of all relevant data sets</span>.</p></span></p><p id="par0365" class="elsevierStylePara elsevierViewall">Data storage should be done in standard format files, FASTQ, BAM and VCF, which can also be used to exchange data with other laboratories. The results of the analysis should be stored together with the process history leading to these results. This history should be as complete as possible, allowing the reproducibility of bioinformatic analysis from FASTQ files. Unfortunately, there is still no international consensus on what information that should be stored. However, storage should be in line with health policies on information storage and common sense.<span class="elsevierStyleDisplayedQuote" id="dsq0130"><p id="spar0180" class="elsevierStyleSimplePara elsevierViewall">Statement 26: <span class="elsevierStyleItalic">In each study, the coverage obtained in the regions of interest should be defined, in which variants can be identified by meeting the established quality criteria. This information on the level of coverage in the regions of interest should be available to the clinician in the report of results, or in accessible digital records, so that the level of uncertainty of the study can be assessed</span>.</p></span></p><p id="par0370" class="elsevierStylePara elsevierViewall">Before initiating any analysis, the region of interest to be sequenced must be defined for each gene (clinical objective to be studied), that is, all the coding regions and preserved <span class="elsevierStyleItalic">splicing</span> sites. The clinical objective depends on the diagnostic test and the previously defined gene panel.<span class="elsevierStyleDisplayedQuote" id="dsq0135"><p id="spar0185" class="elsevierStyleSimplePara elsevierViewall">Statement 27: <span class="elsevierStyleItalic">The requirements of the extent of the report depend on the purpose of the analysis</span>.</p></span></p><p id="par0375" class="elsevierStylePara elsevierViewall">For example, exome sequencing does not require additional analysis to complete coverage in those genomic regions insufficiently covered in the NGS assay in order to achieve a high diagnostic performance; but it must be clearly communicated to the clinician that the test cannot be used to exclude a particular clinical diagnosis. However, when studying a selected panel of genes, it is sought to obtain the greatest possible horizontal and vertical coverage, using, if necessary, Sanger sequencing to complete the regions that are not sufficiently covered. In this way, the study can be used to exclude a clinical diagnosis of suspicion with a lower margin of error.<span class="elsevierStyleDisplayedQuote" id="dsq0140"><p id="spar0190" class="elsevierStyleSimplePara elsevierViewall">Statement 28: <span class="elsevierStyleItalic">Whenever important changes are made in the test; the quality parameters must be verified, and samples already analysed must be re-analysed. The laboratory should define beforehand what type of samples and the number of cases that should be analysed each time the method is updated or improved</span>.</p></span></p><p id="par0380" class="elsevierStylePara elsevierViewall">The capabilities of the diagnostic test should be evaluated in terms of accuracy, analytical sensitivity, analytical specificity and precision. Although its determination in the validation process may be perceived as costly or difficult to carry out, ISO 15189 establishes its study in a strict manner.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Reports of results</span><p id="par0385" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDisplayedQuote" id="dsq0145"><p id="spar0195" class="elsevierStyleSimplePara elsevierViewall">Statement 29: <span class="elsevierStyleItalic">The genetic report of an NGS assay should summarize the patient's identification data and clinical diagnosis. It must also contain a brief description of the test performed, a summary of the results and the main findings on a single page</span>.</p></span></p><p id="par0390" class="elsevierStylePara elsevierViewall">It is essential that the results of NGS be communicated in a clear, consistent and concise manner, since the laboratory reports can be read by genetic experts as well as non-experts. Thus, it is recommended that on the first page of the genetic report the main conclusions with clinical significance be detailed, as well as the test performed and the quality control thereof. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows a model of the structure and content that a results report should have.<span class="elsevierStyleDisplayedQuote" id="dsq0150"><p id="spar0200" class="elsevierStyleSimplePara elsevierViewall">Statement 30: <span class="elsevierStyleItalic">Before carrying out genetic diagnostic studies using NGS technology, it is highly recommended that, following international recommendations, the standard operating procedure includes what type of variants (according to their clinical significance) will be reported/described and how they are going to reflect the results obtained using this technology</span>.</p></span></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0395" class="elsevierStylePara elsevierViewall">There is enough international consensus to classify the identified variants according to the 5-class system proposed by Plon et al.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</span></a> All the pathogenic and probably pathogenic variants identified must be reported (classes 5 and 4, respectively). The information reflected in the report on class 3 variants (variants of unknown significance [VUS]) will depend on the consensus established at local level by the laboratory responsible for the genetic study but must be clearly specified for easy understanding by other clinical or laboratory physicians.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Information management</span><p id="par0400" class="elsevierStylePara elsevierViewall">After the continuous technical advances related to massive sequencing and the optimization of sequencing processes, the main difficulty nowadays relates to solving the interpretation of genomic data within the clinical context. A correct management of the information and knowledge obtained greatly facilitates the process of analysis and interpretation of genomic data, significantly reducing the time required and providing greater accuracy in terms of results, with the interpretation based on firm evidence and reliability criteria.<span class="elsevierStyleDisplayedQuote" id="dsq0155"><p id="spar0205" class="elsevierStyleSimplePara elsevierViewall">Statement 31: <span class="elsevierStyleItalic">It is of great importance to gather in an orderly and computerized way the maximum information about the VUS identified in the genetic diagnosis process with the aim of being able to classify them in the future</span>.</p></span></p><p id="par0405" class="elsevierStylePara elsevierViewall">It is necessary that the process of selection, classification and prioritization of variants is reflected in the standard operating procedures, paying special attention to the following points.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</span></a><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">-</span><p id="par0410" class="elsevierStylePara elsevierViewall">The process of selecting the variants and regions of interest based on their clinical interest, criteria of evidence and reliability of said evidences must be recorded in an orderly manner in databases that facilitate their access, consultation and updating. It is recommended that this process be initiated during the design of the panel, being preserved and systematically reviewed after the corresponding analysis of results.</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">-</span><p id="par0415" class="elsevierStylePara elsevierViewall">The selection criteria and levels of evidence should refer to verified scientific articles and updated and trustworthy databases. The fact that there is a significant percentage of misclassified variants or with contradictory interpretations in public databases should be considered.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">20,21</span></a> Quality criteria must be assigned to the information handled according to the sources consulted and a strict professional evaluation.</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">-</span><p id="par0420" class="elsevierStylePara elsevierViewall">Consensus nomenclature (HGVS, varnomen.hgvs.org)<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> or genomic coordinates must be used, paying special attention to the versions of the reference sequences used, both in the database and in the bioinformatic analysis procedure (transcribed and reference genome).</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">-</span><p id="par0425" class="elsevierStylePara elsevierViewall">The classification of variants for hereditary diseases should be carried out in 5 categories: (1) pathogenic, (2) probably pathogenic, (3) variants of uncertain significance (VUS/VOUS), (4) probably benign and (5) benign, in accordance with international recommendations.<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">23,24</span></a> The levels of evidence and trust should be continually reviewed as mentioned above.</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">-</span><p id="par0430" class="elsevierStylePara elsevierViewall">Alternative criteria should be established to support interpretation, especially in VUS and intermediate categories, such as: allele frequency in the general population and study population, possibility of functional studies, prediction tools in silico, etc.</p></li></ul><span class="elsevierStyleDisplayedQuote" id="dsq0160"><p id="spar0210" class="elsevierStyleSimplePara elsevierViewall">Statement 32: <span class="elsevierStyleItalic">The laboratories must have a well-defined protocol to treat the identification of incidental or secondary findings before implementing the test in the diagnostic routine</span>.</p></span></p><p id="par0435" class="elsevierStylePara elsevierViewall">The occurrence of incidental or secondary findings is relatively common, more so the greater the panel of genes is or in the analysis of exome or complete genome.</p><p id="par0440" class="elsevierStylePara elsevierViewall">These incidental findings may be variants associated with diseases other than those suffered by the patient, even associated with late-onset or predisposing diseases, or variants of response to drugs.</p><p id="par0445" class="elsevierStylePara elsevierViewall">The laboratory must establish a policy of how to act in the identification of this type of findings, which must be defined and explained in the corresponding informed consent and act in accordance with it and with professional recommendations.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleDisplayedQuote" id="dsq0165"><p id="spar0215" class="elsevierStyleSimplePara elsevierViewall">Statement 33: <span class="elsevierStyleItalic">The laboratory is not required to systematically reanalyse “old” results or report new findings</span>.</p></span></p><p id="par0450" class="elsevierStylePara elsevierViewall">Each request for a genetic study represents a contract or agreement at a specific time. Accordingly, the laboratory has the obligation to offer what is known and validated at the precise moment of the request and does not have responsibility for any changes that may occur in the future.</p><p id="par0455" class="elsevierStylePara elsevierViewall">Any reanalysis of data should be understood as a new process for which a new genetic study request would be necessary.<span class="elsevierStyleDisplayedQuote" id="dsq0170"><p id="spar0220" class="elsevierStyleSimplePara elsevierViewall">Statement 34: <span class="elsevierStyleItalic">The laboratory should have a local database including the identified variants of the diseases for which it offers genetic diagnosis to effectively manage that disease's variants</span>.</p></span></p><p id="par0460" class="elsevierStylePara elsevierViewall">Although, as established in Statement 33, the laboratory does not have the obligation to reanalyze “old” results in a systematic way, the review of the clinical meaning of VUS can be requested by the patient or by the responsible clinician at any moment. In fact, it is recommended that during counselling and delivery of results, patients receive a report with VUS that they can consult periodically in the counselling unit, or in any other unit in which they may be treated, regarding possible classification changes of his/her VUS, according to current scientific evidence. To be able to satisfy this demand, the laboratory must maintain a traceability system that allows connecting patients and variants, with the possible changes of clinical interpretation applied.</p><p id="par0465" class="elsevierStylePara elsevierViewall">In case of requesting a VUS update, or alternatively, if the laboratory detects a reclassification of a VUS on its own initiative, a new report must be prepared with the updated clinical meaning of the variant and reported to the clinician responsible for the patient in question. The clinician must assess the implications of this reclassification for the patient and his family, as well as the way to manage the new situation.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Distinction between research and healthcare areas</span><p id="par0470" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDisplayedQuote" id="dsq0175"><p id="spar0225" class="elsevierStyleSimplePara elsevierViewall">Statement 35: <span class="elsevierStyleItalic">A diagnostic genetic study is an analysis aimed at answering a clinical question related to the medical condition of a patient</span>.</p></span><span class="elsevierStyleDisplayedQuote" id="dsq0180"><p id="spar0230" class="elsevierStyleSimplePara elsevierViewall">Statement 36: <span class="elsevierStyleItalic">A genetic research study aims to solve a scientific question through a working hypothesis and may have a limited clinical relevance for the patient included in the project</span>.</p></span></p><p id="par0475" class="elsevierStylePara elsevierViewall">In genetic studies, the line that separates the field of research from the healthcare field has always been diffuse and very difficult to define. New high-performance technologies that allow the simultaneous analysis of large panels of genes, exomes or genomes, further complicate this separation. In any case, it is very important that the scope of the genetic study be defined in advance, what are the expected results and their importance in the management of the patient and their family, as well as the management of the information obtained. These aspects should always be included in the protocol of the research project as well as in the corresponding standardized procedure of the diagnostic care laboratory, depending on the case.</p><p id="par0480" class="elsevierStylePara elsevierViewall">The patient must have been duly informed of the scope of the genetic study to which he will be subjected and sign the required informed consent for the diagnostic study. In addition, the patient may give his/her informed consent by signing an independent and specific consent document, either f or a specific research study or to keep the excess biological material from the diagnosis in a Biobank for their possible use in research projects approved by the corresponding scientific and ethical committees.<span class="elsevierStyleDisplayedQuote" id="dsq0185"><p id="spar0235" class="elsevierStyleSimplePara elsevierViewall">Statement 37: <span class="elsevierStyleItalic">The results of a diagnostic genetic study using complete exome or genome sequencing can generate new working hypotheses for research projects</span>.</p></span><span class="elsevierStyleDisplayedQuote" id="dsq0190"><p id="spar0240" class="elsevierStyleSimplePara elsevierViewall">Statement 38: <span class="elsevierStyleItalic">Genetic studies whose main objective is the diagnosis of a patient must be performed in an accredited clinical laboratory</span>.</p></span></p><p id="par0485" class="elsevierStylePara elsevierViewall">The use of data obtained from exomes or genomes by NGS in the context of care diagnosis is acceptable, provided that the objective of such studies is to obtain a genetic diagnosis and the analysis of the results is limited only to those genes in which there is scientific evidence of its association with the disease.<span class="elsevierStyleDisplayedQuote" id="dsq0195"><p id="spar0245" class="elsevierStyleSimplePara elsevierViewall">Statement 39: <span class="elsevierStyleItalic">The research results must be confirmed by an accredited clinical laboratory before being reported to the patient</span>.</p></span></p><p id="par0490" class="elsevierStylePara elsevierViewall">Patients and families participating in a research project should be aware that the results of the study can reveal a possible diagnosis or prediction of genetic risk to one or several diseases. When biological material deposited in accredited Biobanks is used, this material may be available in accordance with the operating regulations of said Biobank. In such cases, both the informed consent for a specific research project and that of the Biobank should contemplate the right to know, or not know, the results obtained and how to manage any genetic information with relevant clinical impact obtained as a result of research projects. The informed consent of the patient in relation to these aspects must be established in said informed consents.</p><p id="par0495" class="elsevierStylePara elsevierViewall">The results obtained from research projects that may be clinically relevant can only be transferred to the patient's clinical history after the confirmation of said results in the diagnostic context of a clinical laboratory.<span class="elsevierStyleDisplayedQuote" id="dsq0200"><p id="spar0250" class="elsevierStyleSimplePara elsevierViewall">Statement 40: <span class="elsevierStyleItalic">All variants detected in genes related to disease, in affected patients, should be shared in regional, national or international databases</span>.</p></span></p><p id="par0500" class="elsevierStylePara elsevierViewall">One of the main objectives set at an international level by scientific and professional societies in the context of genetic studies is the interpretation of the clinical significance of the genetic variants obtained. For this, it is essential to share in public databases the variants obtained by each laboratory, the criteria and arguments considered for their classification and the associated clinical phenotypes. The information must be anonymous, and patients must have signed the required informed consent, in order to make this anonymous information available to the scientific and medical community. Sharing knowledge allows us to advance in a faster and safer way towards a better diagnosis and better management of families with genetic risk of cancer.<span class="elsevierStyleDisplayedQuote" id="dsq0205"><p id="spar0255" class="elsevierStyleSimplePara elsevierViewall">Statement 41: <span class="elsevierStyleItalic">The frequencies of all genetic variants detected in healthy individuals should be shared in regional, national or international databases</span>.</p></span></p><p id="par0505" class="elsevierStylePara elsevierViewall">When a research project, or even a diagnostic study, requires the study of healthy individuals, parents or other unaffected relatives, the information of the variants detected in these studies may be useful for the classification of variants. Given that these are healthy individuals and there is no sensitive clinical content, and that information about the frequency of the variants can improve the diagnosis, this information should be shared.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusions</span><p id="par0510" class="elsevierStylePara elsevierViewall">The implementation of NGS in the genetic diagnosis of hereditary cancer predisposition is a complex process that requires a thorough planning of the different key aspects that comprise it, both in terms of purely technical aspects and those related to genetic counselling.</p><p id="par0515" class="elsevierStylePara elsevierViewall">It is important to define with precision the objective and scope of the genetic studies that are proposed, which will determine to a large extent the design of the assay.</p><p id="par0520" class="elsevierStylePara elsevierViewall">The analytical and clinical validation of the procedures and the clinical utility of the genetic study are the cornerstone in the implementation of the new NGS technology.</p><p id="par0525" class="elsevierStylePara elsevierViewall">The management of the information obtained and the generation of clear and precise results reports are especially relevant with NGS, due to the need to properly handle the uncertainty generated by the VUS and incidental findings.</p><p id="par0530" class="elsevierStylePara elsevierViewall">All the particulars of NGS must be included in the informed consent and must be adequately treated in the genetic counselling process.</p><p id="par0535" class="elsevierStylePara elsevierViewall">Finally, it is important to restrict this research to a purely healthcare scope. Diagnostic reports must always be issued by accredited clinical laboratories.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Authorship/collaborators</span><p id="par0540" class="elsevierStylePara elsevierViewall">CL and JLS coordinated the working group, wrote the proposal and modified all aspects of the guidelines that were requested by the working group and the sections and committees of the societies that sponsor the document for publication.</p><p id="par0545" class="elsevierStylePara elsevierViewall">IB, OD, JGP, IL, MR, CL and JLS formed part of the working group, preparing the different sections of the document and making the necessary modifications.</p><p id="par0550" class="elsevierStylePara elsevierViewall">GM and ES acted on behalf of <span class="elsevierStyleItalic">The EuroGentest/ESHG working group on Diagnostic NGS</span> and gave the go-ahead to the document.</p><p id="par0555" class="elsevierStylePara elsevierViewall">Hereditary Cancer Committee of the AEGH: Adela Castillejo Castillo, Marta Pineda Riu, Atocha Romero Alfonso, José Luis Soto Martínez.</p><p id="par0560" class="elsevierStylePara elsevierViewall">The draft of the document was reviewed and approved by the following sections/committees and endorsed by the boards of directors of the respective companies:</p><p id="par0565" class="elsevierStylePara elsevierViewall">Section of Hereditary Cancer of the SEOM: Elena Aguirre Ortega, Raquel Andrés Conejero, Orland Díez Gibert, Begoña Graña Suarez, Gemma Llort Pursals, Montserrat Muñoz Mateu, Mauro Javier Oruezábal Moreno, Ana Beatriz Sánchez Heras, Raquel Serrano Blanch, Alexandre Teulé Vega.</p><p id="par0570" class="elsevierStylePara elsevierViewall">Genetics Committee of the SEQC-ML: Concepción Alonso Cerezo, Pilar Carrasco Salas, Ana Cuesta Peredo, Orland Diez Gibert, Begoña Ezquieta Zubicaray, Macher Manzano Fairy, Jesus Molano Mateos, Josep Oriola Ambròs, Raquel Rodriguez López, Atocha Romero Alfonso, Ana Mª Sanchez de Abajo, María Santamaría González, Cristina Torreira Banza.</p><p id="par0575" class="elsevierStylePara elsevierViewall">IB, JGP and CL are part of the board of directors of the AEGH.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Funding</span><p id="par0580" class="elsevierStylePara elsevierViewall">No funding has been received for the preparation of the guidelines.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interests</span><p id="par0585" class="elsevierStylePara elsevierViewall">The authors declare that they do not have a conflict of interest related to the content of the guidelines.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:19 [ 0 => array:3 [ "identificador" => "xres1063467" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1011670" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1063468" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1011671" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Scope and objective" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Methodology" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Method of preparation, revision, approval and update of the guidelines" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Population and professionals to whom the guidelines are addressed" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Review and update of the guidelines" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Structure of the guidelines and levels of evidence" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Clinical and diagnostic utility" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Informed consent and pretest and post-test genetic counselling" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Validation of analytical procedures" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Reports of results" ] 11 => array:2 [ "identificador" => "sec0060" "titulo" => "Information management" ] 12 => array:2 [ "identificador" => "sec0065" "titulo" => "Distinction between research and healthcare areas" ] 13 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusions" ] 14 => array:2 [ "identificador" => "sec0075" "titulo" => "Authorship/collaborators" ] 15 => array:2 [ "identificador" => "sec0080" "titulo" => "Funding" ] 16 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of interests" ] 17 => array:2 [ "identificador" => "xack359944" "titulo" => "Acknowledgements" ] 18 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-09-25" "fechaAceptado" => "2017-12-14" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1011670" "palabras" => array:5 [ 0 => "NGS" 1 => "Next generation sequencing" 2 => "Hereditary cancer" 3 => "Genetic diagnosis" 4 => "Consensus document" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1011671" "palabras" => array:5 [ 0 => "NGS" 1 => "Secuenciación masiva" 2 => "Cáncer hereditario" 3 => "Diagnóstico genético" 4 => "Documento de consenso" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Genetic diagnosis of hereditary cancer syndromes offers the opportunity to establish more effective predictive and preventive measures for the patient and their families. The ultimate objective is to decrease cancer morbidity and mortality in high genetic risk families. Next Generation Sequencing (NGS) offers an important improvement in the efficiency of genetic diagnosis, allowing an increase in diagnostic yield with a substantial reduction in response times and economic costs. Consequently, the implementation of this new technology is a great opportunity for improvement in the clinical management of affected families.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The aim of these guidelines is to establish a framework of useful recommendations for planned and controlled implementation of NGS in the context of hereditary cancer. These will help to consolidate the strengths and opportunities offered by this technology, and minimize the weaknesses and threats which may derive from its use.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The recommendations of international societies have been adapted to our environment, taking the Spanish context into account at organizational and juridical levels.</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Forty-one statements are grouped under six headings: clinical and diagnostic utility, informed consent and genetic counselling pre-test and post-test, validation of analytical procedures, results report, management of information and distinction between research and clinical context.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">This guide has been developed by the Spanish Association of Human Genetics (AEGH), the Spanish Society of Laboratory Medicine (SEQC-ML) and the Spanish Society of Medical Oncology (SEOM).</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El diagnóstico genético de los síndromes de cáncer hereditario ofrece la oportunidad de establecer unas medidas de predicción/prevención eficaces en el paciente y sus familiares que se traducen en una disminución de la morbimortalidad por cáncer en las familias de alto riesgo genético. La secuenciación masiva (NGS) ofrece una considerable mejora de la eficiencia del diagnóstico genético, permitiendo un aumento del rendimiento diagnóstico con una reducción sustancial del tiempo de respuesta y costes económicos. En consecuencia, la implementación de esta nueva tecnología es una gran oportunidad de mejora en el manejo clínico de las familias afectas.</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El objetivo de la presente guía es establecer un marco de recomendaciones útiles para una implementación planificada y controlada de la NGS en el contexto de la predisposición hereditaria a cáncer, que permita potenciar las fortalezas y oportunidades que ofrece dicha tecnología y minimizar las debilidades y amenazas que puedan derivarse de su uso.</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Está inspirada en las recomendaciones de sociedades internacionales, habiendo sido adaptada a nuestro entorno, y teniendo en cuenta aspectos coyunturales a nivel organizativo y biojurídico.</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se aportan 41 declaraciones agrupadas en 6 apartados: utilidad clínica y diagnóstica, consentimiento informado y asesoramiento genético pretest y postest, validación de los procedimientos analíticos, informe de resultados, gestión de la información y distinción entre ámbito de investigación y ámbito asistencial.</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Esta guía ha sido elaborada por la Asociación Española de Genética Humana (AEGH), la Sociedad Española de Medicina de Laboratorio (SEQC-ML) y la Sociedad Española de Oncología Médica (SEOM).</p></span>" ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Soto JL, Blanco I, Díez O, García Planells J, Lorda I, Matthijs G, et al. Documento de consenso sobre la implementación de la secuenciación masiva de nueva generación en el diagnóstico genético de la predisposición hereditaria al cáncer. Med Clin (Barc). 2018;151:80.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Spanish Association of Human Genetics (AEGH), Spanish Society of Laboratory Medicine (SEQC-ML) and Spanish Society of Medical Oncology (SEOM).</p>" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0600" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0095" ] ] ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">1. Identification of the laboratory where the genetic study is carried out</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">2. Identification of the applicant and recipient</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">3. Report ID No.</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">4. Identification of the individual</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">5. Identification of the family</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">6 Indication</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Study requested. For example, hereditary breast and ovarian cancer</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">7 Reason for study</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Personal and family history of cancer that motivate suspicion</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">8 Identification of the type of specimen</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">For example, blood, tumour, saliva, skin, genomic DNA, etc.</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">9. Dates of obtaining the specimen and issuing the result</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">10 Type of study carried out</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">This section should contain information on the panel's own design, and therefore if it is based on amplicons or enrichment, and the list of genes analyzed. In the case of using a commercial kit, mention must be made of the reference number/name of the kit and the commercial company with which the libraries were prepared, as well as NGS equipment used</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">In addition, the validation method used must be specified (e.g., Sanger sequencing). If the result has not been validated by an alternative method, it must be clearly specified</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">11. Result</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">In this section, the conclusion of the result of the analytical determination made must be established in a clear, concise and precise manner.</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">For example: A heterozygous pathogenic variant has been detected: c.XXXXX; p.XXXX</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Reference sequence: LRG_218t1. Nomenclature used: HGVS</span> (<a class="elsevierStyleInterRef" target="_blank" id="intr0005" href="http://varnomen.hgvs.org/"><span class="elsevierStyleItalic">http://varnomen.hgvs.org/</span></a><span class="elsevierStyleItalic">)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">12 Results interpretation</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Description of the variant (s) of clinical interest, their biological and clinical significance. Arguments on the clinical significance classification (databases, bibliographic references and/or lines of evidence that support their classification)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">13. Identification of the professional responsible for the validation of the report</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">14. Annex</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Examples of annexes</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Annex 1: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Methodology and technical limitations \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Methodology (DNA extraction, generation of libraries, sequencing, bioinformatic analysis of data, interpretation and prioritization of results) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Databases consulted; prediction programmes in silico; technical limitations \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Annex 2: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Parameters of study quality \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Coverage of genes under study \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Annex 3: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span> List of variants detected in the study \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1813196.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0260" class="elsevierStyleSimplePara elsevierViewall">Minimum content of a results report from a <span class="elsevierStyleItalic">next generation sequencing</span> (NGS) panel of genes. It is recommended to include all the essential information on the first page of the results report (points 1 to 13). Technical and quality details of the assay, as well as other useful information that may be considered, can be attached in the form of annexes.</p>" ] ] 1 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 589608 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0130" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for diagnostic next-generation sequencing" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Matthijs" 1 => "E. Souche" 2 => "M. Alders" 3 => "A. Corveleyn" 4 => "S. Eck" 5 => "I. Feenstra" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ejhg.2015.226" "Revista" => array:6 [ "tituloSerie" => "Eur J Hum Genet" "fecha" => "2016" "volumen" => "24" "paginaInicial" => "2" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26508566" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0135" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Best practice guidelines for the use of next-generation sequencing applications in genome diagnostics: a national collaborative study of Dutch genome diagnostic laboratories" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.M. Weiss" 1 => "B. van der Zwaag" 2 => "J.D.H. Jongbloed" 3 => "M.J. Vogel" 4 => "H.T. Brggenwirth" 5 => "R.H. Lekanne Deprez" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/humu.22368" "Revista" => array:6 [ "tituloSerie" => "Hum Mutat" "fecha" => "2013" "volumen" => "34" "paginaInicial" => "1313" "paginaFinal" => "1321" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23776008" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0140" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Ellard S, Lindsay H, Camm N, Watson C, Abbs S, Wallis Y, et al. Practice guidelines for targeted next generation sequencing analysis and interpretation. Association for Clinical Genetic Science (ACGS). British Society for Genetic Medicine. Available from: <a id="intr0040" class="elsevierStyleInterRef" href="http://www.acgs.uk.com/media/774807/bpg_for_targeted_next_generation_sequencing_may_2014_final.pdf">http://www.acgs.uk.com/media/774807/bpg_for_targeted_next_generation_sequencing_may_2014_final.pdf</a> [accessed 29.01.18]." ] ] ] 3 => array:3 [ "identificador" => "bib0145" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "ACMG Board of Directors" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/gim.2015.41" "Revista" => array:6 [ "tituloSerie" => "Genet Med" "fecha" => "2015" "volumen" => "17" "paginaInicial" => "505" "paginaFinal" => "507" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25764213" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0150" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ACMG clinical laboratory standards for next-generation sequencing" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Working Group of the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee" "etal" => true "autores" => array:6 [ 0 => "H.L. Rehm" 1 => "S.J. Bale" 2 => "P. Bayrak-Toydemir" 3 => "J.S. Berg" 4 => "K.K. Brown" 5 => "J.L. Deignan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/gim.2013.92" "Revista" => array:6 [ "tituloSerie" => "Genet Med" "fecha" => "2013" "volumen" => "15" "paginaInicial" => "733" "paginaFinal" => "747" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23887774" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0155" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulating whole exome sequencing as a diagnostic test" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "V. Lapin" 1 => "L.C. Mighion" 2 => "P. da Silva" 3 => "Y. Cuperus" 4 => "L.J.H. Bean" 5 => "M.R. Hegde" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00439-016-1677-3" "Revista" => array:6 [ "tituloSerie" => "Hum Genet" "fecha" => "2016" "volumen" => "135" "paginaInicial" => "655" "paginaFinal" => "673" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27167135" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0160" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Consorcio AGREE. Instrumento AGREE II: instrumento para la evaluación de guías de práctica clínica. Available from: <a id="intr0045" class="elsevierStyleInterRef" href="http://www.guiasalud.es/contenidos/documentos/Guias_Practica_Clinica/Spanish-AGREE-II">http://www.guiasalud.es/contenidos/documentos/Guias_Practica_Clinica/Spanish-AGREE-II</a> [accessed 29.01.18]." ] ] ] 7 => array:3 [ "identificador" => "bib0165" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Ferlay" 1 => "I. Soerjomataram" 2 => "R. Dikshit" 3 => "S. Eser" 4 => "C. Mathers" 5 => "M. Rebelo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ijc.29210" "Revista" => array:6 [ "tituloSerie" => "Int J Cancer" "fecha" => "2015" "volumen" => "136" "paginaInicial" => "E359" "paginaFinal" => "E386" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25220842" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0170" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "GeneReviews. Available from: <a id="intr0050" class="elsevierStyleInterRef" href="https://www.ncbi.nlm.nih.gov/books/NBK1116/">https://www.ncbi.nlm.nih.gov/books/NBK1116/</a> [accessed 29.01.18]." ] ] ] 9 => array:3 [ "identificador" => "bib0175" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Orphanet. Available from: <a id="intr0055" class="elsevierStyleInterRef" href="http://www.orpha.net/consor4.01/www/cgi-bin/?lng=ES">http://www.orpha.net/consor4.01/www/cgi-bin/?lng=ES</a> [accessed 29.01.18]." ] ] ] 10 => array:3 [ "identificador" => "bib0180" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Concise handbook of familial cancer susceptibility syndromes—second edition" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.L. Lindor" 1 => "C.J. McMaster" 2 => "M.H. Lindor" 3 => "M. Greene" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Natl Cancer Inst Monogr" "fecha" => "2008" "volumen" => "38" "paginaInicial" => "3" "paginaFinal" => "93" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0185" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "American Society of Clinical Oncology Policy Statement Update: genetic and genomic testing for cancer susceptibility" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.E. Robson" 1 => "A.R. Bradbury" 2 => "B. Arun" 3 => "S.M. Domchek" 4 => "J.M. Ford" 5 => "H.L. Hampel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2015.63.0996" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2015" "volumen" => "33" "paginaInicial" => "3660" "paginaFinal" => "3667" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26324357" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0190" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Castellanos" 1 => "B. Gel" 2 => "I. Rosas" 3 => "E. Tornero" 4 => "S. Santín" 5 => "R. Pluvinet" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/srep39348" "Revista" => array:5 [ "tituloSerie" => "Sci Rep" "fecha" => "2017" "volumen" => "7" "paginaInicial" => "39348" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28051113" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0195" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer Susceptibility gene mutations in individuals with colorectal cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.B. Yurgelun" 1 => "M.H. Kulke" 2 => "C.S. Fuchs" 3 => "B.A. Allen" 4 => "H. Uno" 5 => "J.L. Hornick" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2016.71.0012" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2017" "volumen" => "35" "paginaInicial" => "1086" "paginaFinal" => "1095" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28135145" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0200" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "OCEBM Levels of Evidence Working Group. The Oxford Levels of Evidence 2. Oxford Centre for Evidence-Based Medicine. Available from: <a id="intr0060" class="elsevierStyleInterRef" href="http://www.cebm.net/index.aspx?o=5653">http://www.cebm.net/index.aspx?o=5653</a> [accessed 29.01.18]." ] ] ] 15 => array:3 [ "identificador" => "bib0205" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ACCE: a model process for evaluating data on emerging genetic tests" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.E. Haddow" 1 => "G.E. Palomaki" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:4 [ "titulo" => "Human Genome Epidemiology: a scientific foundation for using genetic information to improve health and prevent disease" "paginaInicial" => "217" "paginaFinal" => "233" "serieFecha" => "2003" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0210" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A standardized framework for the validation and verification of clinical molecular genetic tests" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.J. Mattocks" 1 => "M.A. Morris" 2 => "G. Matthijs" 3 => "E. Swinnen" 4 => "A. Corveleyn" 5 => "E. Dequeker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ejhg.2010.101" "Revista" => array:6 [ "tituloSerie" => "Eur J Hum Genet" "fecha" => "2010" "volumen" => "18" "paginaInicial" => "1276" "paginaFinal" => "1288" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20664632" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0215" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "IARC Unclassified Genetic Variants Working Group" "etal" => true "autores" => array:6 [ 0 => "S.E. Plon" 1 => "D.M. Eccles" 2 => "D. Easton" 3 => "W.D. Foulkes" 4 => "M. Genuardi" 5 => "M.S. Greenblatt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/humu.20880" "Revista" => array:6 [ "tituloSerie" => "Hum Mutat" "fecha" => "2008" "volumen" => "29" "paginaInicial" => "1282" "paginaFinal" => "1291" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18951446" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0220" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Standards and guidelines for the interpretation and reporting of sequence variants in cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.M. Li" 1 => "M. Datto" 2 => "E.J. Duncavage" 3 => "S. Kulkarni" 4 => "N.I. Lindeman" 5 => "S. Roy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jmoldx.2016.10.002" "Revista" => array:6 [ "tituloSerie" => "J Mol Diagn" "fecha" => "2017" "volumen" => "19" "paginaInicial" => "4" "paginaFinal" => "23" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27993330" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0225" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L.M. Amendola" 1 => "G.P. Jarvik" 2 => "M.C. Leo" 3 => "H.M. McLaughlin" 4 => "Y. Akkari" 5 => "M.D. Amaral" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ajhg.2016.03.024" "Revista" => array:6 [ "tituloSerie" => "Am J Hum Genet" "fecha" => "2016" "volumen" => "98" "paginaInicial" => "1067" "paginaFinal" => "1076" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27181684" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0230" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ClinGen—the clinical genome resource" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.L. Rehm" 1 => "J.S. Berg" 2 => "L.D. Brooks" 3 => "C.D. Bustamante" 4 => "J.P. Evans" 5 => "M.J. Landrum" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMsr1406261" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2015" "volumen" => "372" "paginaInicial" => "2235" "paginaFinal" => "2242" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26014595" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0235" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nomenclature for the description of human sequence variations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.T. Den Dunnen" 1 => "S.E. Antonarakis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Hum Genet" "fecha" => "2001" "volumen" => "109" "paginaInicial" => "121" "paginaFinal" => "124" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11479744" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0240" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Richards" 1 => "N. Aziz" 2 => "S. Bale" 3 => "D. Bick" 4 => "S. Das" 5 => "J. Gastier-Foster" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/gim.2015.30" "Revista" => array:6 [ "tituloSerie" => "Genet Med" "fecha" => "2015" "volumen" => "17" "paginaInicial" => "405" "paginaFinal" => "423" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25741868" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0245" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B.A. Thompson" 1 => "A.B. Spurdle" 2 => "J.-P. Plazzer" 3 => "M.S. Greenblatt" 4 => "K. Akagi" 5 => "F. Al-Mulla" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ng.2854" "Revista" => array:6 [ "tituloSerie" => "Nat Genet" "fecha" => "2014" "volumen" => "46" "paginaInicial" => "107" "paginaFinal" => "115" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24362816" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0250" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.C. Green" 1 => "J.S. Berg" 2 => "W.W. Grody" 3 => "S.S. Kalia" 4 => "B.R. Korf" 5 => "C.L. Martin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/gim.2013.73" "Revista" => array:6 [ "tituloSerie" => "Genet Med" "fecha" => "2013" "volumen" => "15" "paginaInicial" => "565" "paginaFinal" => "574" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23788249" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack359944" "titulo" => "Acknowledgements" "texto" => "<p id="par0590" class="elsevierStylePara elsevierViewall">The authors wish to thank Drs. Juan Cruz Cigudosa, María Pia Gallano Petit, and Laura Valle Velasco for their collaboration in reviewing the document as external experts in accordance with the AGREE II protocol.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015100000002/v1_201807220502/S2387020618302195/v1_201807220502/en/main.assets" "Apartado" => array:4 [ "identificador" => "46796" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Consensus statement" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015100000002/v1_201807220502/S2387020618302195/v1_201807220502/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020618302195?idApp=UINPBA00004N" ]
Year/Month | Html | Total | |
---|---|---|---|
2023 March | 3 | 0 | 3 |