Parsons MT 1 , Tudini E 1 , Li H 2 , Hahnen E 3 , Wappenschmidt B 3 , Feliubadaló L 4 Show all authors , Aalfs CM 5 , Agata S 6 , Aittomäki K 7 , Alducci E 6 , Alonso-Cerezo MC 8 , Arnold N 9 , Auber B 10 , Austin R 11 , Azzollini J 12 , Balmaña J 13 , Barbieri E 14 , Bartram CR 15 , Blanco A 16 , Blümcke B 3 , Bonache S 17 , Bonanni B 18 , Borg Å 19 , Bortesi B 20 , Brunet J 4 , Bruzzone C 21 , Bucksch K 22 , Cagnoli G 12 , Caldés T 23 , Caliebe A 24 , Caligo MA 25 , Calvello M 18 , Capone GL 26 , Caputo SM 27 , Carnevali I 28 , Carrasco E 13 , Caux-Moncoutier V 27 , Cavalli P 29 , Cini G 30 , Clarke EM 1 , Concolino P 31 , Cops EJ 32 , Cortesi L 14 , Couch FJ 33 , Darder E 4 , de la Hoya M 23 , Dean M 34 , Debatin I 35 , Del Valle J 4 , Delnatte C 36 , Derive N 27 , Diez O 17 , Ditsch N 37 , Domchek SM 38 , Dutrannoy V 39 , Eccles DM 40 , Ehrencrona H 41 , Enders U 22 , Evans DG 42 , Farra C 43 , Faust U 44 , Felbor U 45 , Feroce I 18 , Fine M 46 , Foulkes WD 47 , Galvao HCR 48 , Gambino G 25 , Gehrig A 49 , Gensini F 26 , Gerdes AM 50 , Germani A 51 , Giesecke J 3 , Gismondi V 21 , Gómez C 4 , Gómez Garcia EB 52 , González S 4 , Grau E 4 , Grill S 53 , Gross E 37 , Guerrieri-Gonzaga A 18 , Guillaud-Bataille M 54 , Gutiérrez-Enríquez S 17 , Haaf T 49 , Hackmann K 55 , Hansen TVO 50 , Harris M 56 , Hauke J 3 , Heinrich T 44 , Hellebrand H 53 , Herold KN 57 , Honisch E 58 , Horvath J 59 , Houdayer C 60 , Hübbel V 3 , Iglesias S 4 , Izquierdo A 4 , James PA 32 , Janssen LAM 61 , Jeschke U 37 , Kaulfuß S 62 , Keupp K 3 , Kiechle M 53 , Kölbl A 37 , Krieger S 63 , Kruse TA 64 , Kvist A 19 , Lalloo F 65 , Larsen M 3 , Lattimore VL 66 , Lautrup C 67 , Ledig S 59 , Leinert E 68 , Lewis AL 69 , Lim J 70 , Loeffler M 22 , López-Fernández A 13 , Lucci-Cordisco E 71 , Maass N 9 , Manoukian S 12 , Marabelli M 18 , Matricardi L 6 , Meindl A 37 , Michelli RD 48 , Moghadasi S 61 , Moles-Fernández A 17 , Montagna M 6 , Montalban G 17 , Monteiro AN 72 , Montes E 4 , Mori L 73 , Moserle L 6 , Müller CR 49 , Mundhenke C 9 , Naldi N 20 , Nathanson KL 38 , Navarro M 4 , Nevanlinna H 74 , Nichols CB 75 , Niederacher D 58 , Nielsen HR 64 , Ong KR 76 , Pachter N 75 , Palmero EI 77 , Papi L 26 , Pedersen IS 78 , Peissel B 12 , Perez-Segura P 23 , Pfeifer K 53 , Pineda M 4 , Pohl-Rescigno E 3 , Poplawski NK 46 , Porfirio B 26 , Quante AS 53 , Ramser J 53 , Reis RM 77 , Revillion F 79 , Rhiem K 3 , Riboli B 29 , Ritter J 39 , Rivera D 21 , Rofes P 4 , Rump A 55 , Salinas M 4 , Sánchez de Abajo AM 80 , Schmidt G 10 , Schoenwiese U 22 , Seggewiß J 59 , Solanes A 4 , Steinemann D 10 , Stiller M 81 , Stoppa-Lyonnet D 27 , Sullivan KJ 82 , Susman R 11 , Sutter C 15 , Tavtigian SV 83 , Teo SH 70 , Teulé A 4 , Thomassen M 64 , Tibiletti MG 28 , Tischkowitz M 84 , Tognazzo S 6 , Toland AE 85 , Tornero E 4 , Törngren T 19 , Torres-Esquius S 13 , Toss A 14 , Trainer AH 32 , Tucker KM 86 , van Asperen CJ 61 , van Mackelenbergh MT 9 , Varesco L 21 , Vargas-Parra G 4 , Varon R 39 , Vega A 16 , Velasco Á 4 , Vesper AS 58 , Viel A 30 , Vreeswijk MPG 87 , Wagner SA 88 , Waha A 3 , Walker LC 66 , Walters RJ 1 , Wang-Gohrke S 68 , Weber BHF 89 , Weichert W 90 , Wieland K 22 , Wiesmüller L 68 , Witzel I 91 , Wöckel A 92 , Woodward ER 42 , Zachariae S 22 , Zampiga V 93 , Zeder-Göß C 37 , Investigators K 94 , Lázaro C 4 , De Nicolo A 95 , Radice P 96 , Engel C 22 , Schmutzler RK 3 , Goldgar DE 97 , Spurdle AB 1

Affiliations 

  • 1 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 2 Cancer Control and Population Science, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
  • 3 Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • 4 Hereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain
  • 5 Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands
  • 6 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, IRCCS, Padua, Italy
  • 7 Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 8 Clinical Genetics, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria, Madrid, Spain
  • 9 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
  • 10 Institute of Human Genetics, Hannover Medical School, Hannover, Germany
  • 11 Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia
  • 12 Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
  • 13 High Risk and Cancer Prevention Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
  • 14 Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy
  • 15 Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
  • 16 Fundación Pública galega Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain
  • 17 Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
  • 18 Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy
  • 19 Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
  • 20 Division of Oncology, University Hospital of Parma, Parma, Italy
  • 21 Unit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
  • 22 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 23 Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain
  • 24 Institute of Human Genetics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
  • 25 SOD Genetica Molecolare, University Hospital, Pisa, Italy
  • 26 Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy
  • 27 Service de Génétique, Institut Curie, Paris, France
  • 28 UO Anatomia Patologica, Ospedale di Circolo ASST Settelaghi, Varese, Italy
  • 29 Servizio di Genetica, ASST di Cremona, Cremona, Italy
  • 30 Division of Functional Onco-genomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
  • 31 Fondazione Policlinico Universitario A.Gemelli, IRCCS, Rome, Italy
  • 32 Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  • 33 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 34 Laboratory of Translational Genomics, DCEG, National Cancer Institute, Gaithersburg, Maryland
  • 35 Institute of Human Genetics, University Hospital Ulm, Ulm, Germany
  • 36 Laboratoire de Genetique Moleculaire, CHU Nantes, Nantes, France
  • 37 Department of Gynecology and Obstetrics, University of Munich, Munich, Germany
  • 38 Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
  • 39 Institute of Medical and Human Genetics, Charité -Universitätsmedizin Berlin, Berlin, Germany
  • 40 Faculty of Medicine, University of Southampton, Southampton, UK
  • 41 Department of Clinical Genetics and Pathology, Laboratory Medicine, Office for Medical Services - Region Skåne, Lund, Sweden
  • 42 Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK
  • 43 Medical Genetics, American University of Beirut Medical Center, Beirut, Lebanon
  • 44 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
  • 45 Institute of Human Genetics, University Medicine Greifswald, Greifswald, Germany
  • 46 Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia
  • 47 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada
  • 48 Oncogenetics Department, Barretos Cancer Hospital, São Paulo, Brazil
  • 49 Department of Human Genetics, University of Würzburg, Würzburg, Germany
  • 50 Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 51 Department of Clinical and Molecular Medicine, Sant'Andrea University Hospital, Sapienza University, Rome, Italy
  • 52 Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
  • 53 Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen, Universität München, Munich, Germany
  • 54 Departement de Biopathologie, Gustave Roussy, Universite Paris-Saclay, Villejuif, France
  • 55 Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
  • 56 Familial Cancer Centre, Monash Health, Clayton, Australia
  • 57 The City of Hope, Duarte, California
  • 58 Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  • 59 Institute of Human Genetics, University of Münster, Münster, Germany
  • 60 Department of Genetics, F76000 and Normandy University, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, Rouen, France
  • 61 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  • 62 Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
  • 63 Laboratoire de Biologie Clinique et Oncologique, Centre Francois Baclesse, Caen, France
  • 64 Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
  • 65 Genomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK
  • 66 Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
  • 67 Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark
  • 68 Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
  • 69 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  • 70 Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 71 UOC Genetica Medica, Fondazione Policlinico Universitario A.Gemelli IRCCS and Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy
  • 72 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida
  • 73 Department of Clinical and Experimental Science, University of Brescia c/o 2nd Internal Medicine, Hospital of Brescia, Brescia, Italy
  • 74 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 75 Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia
  • 76 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, UK
  • 77 Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil
  • 78 Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
  • 79 Laboratoire d'Oncogenetique Moleculaire Humaine, Centre Oscar Lambret, Lille, France
  • 80 Servicio de Análisis Clínicos y Bioquímica Clínica, Complejo Hospitalario, Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaría, Spain
  • 81 Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany
  • 82 Genetic Health Service NZ- Northern Hub, Auckland District Health Board, Auckland, New Zealand
  • 83 Department of Oncological Services, University of Utah School of Medicine, Salt Lake City, Utah
  • 84 Department of Medical Genetics, University of Cambridge, Cambridge, UK
  • 85 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio
  • 86 Prince of Wales Clinical School, University of NSW, Sydney, New South Wales, Australia
  • 87 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  • 88 Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, Frankfurt, Germany
  • 89 Institute of Human Genetics, University Regensburg, Regensberg, Germany
  • 90 Institute of Pathology, Technische Universität München, Munich, Germany
  • 91 Department of Gynecology, University Medical Center Hamburg, Hamburg, Germany
  • 92 Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
  • 93 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
  • 94 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  • 95 Cancer Genomics Program, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
  • 96 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 97 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah
Hum. Mutat., 2019 Sep;40(9):1557-1578.
PMID: 31131967 DOI: 10.1002/humu.23818

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.