Article
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations
Affiliations
Organisations
- (1) Harvard University, grid.38142.3c
- (2) Sheba Medical Center, grid.413795.d
- (3) German Cancer Research Center, grid.7497.d
- (4) Center for Clinical Cancer Genetics and Global Health University of Chicago Chicago USA
- (5) The Hong Kong Hereditary Breast Cancer Family Registry Cancer Genetics Center Hong Kong Sanatorium and Hospital Hong Kong China
- (6) National Institute of Oncology, grid.419617.c
- (7) University of Buenos Aires, grid.7345.5
- (8) Cancer Research Initiatives Foundation, grid.427737.2
- (9) Department of Clinical Genetics Odense University Hospital Odense Denmark
- (10) Division of Clinical Cancer Genomics City of Hope Cancer Center California USA
- (11) Division of Molecular Pathology Department of Pathology Hong Kong Sanatorium & Hospital Happy Valley Hong Kong
- (12) Department of Laboratory Medicine and Pathology and Health Sciences Research Rochester USA
- (13) Department of Dermatology University of Utah School of Medicine Salt Lake City USA
- (14) Molecular Oncology Research Center Barretos Cancer Hospital São Paulo Brazil
- (15) Department of Preventive Medicine Seoul National University College of Medicine Seoul Korea
- (16) Seoul National University, grid.31501.36
- (17) Pontificia Universidad Javeriana, grid.41312.35
- (18) Cancer Genetics Laboratory, Department of Genetics University of Pretoria South Africa
- (19) University of Cambridge, grid.5335.0
- (20) QIMR Berghofer Medical Research Institute, grid.1049.c
- (21) Department of Clinical Genetics Academic Medical Center Amsterdam The Netherlands
- (22) City Of Hope National Medical Center, grid.410425.6
- (23) Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds UK
- (24) Istituto Oncologico Veneto, grid.419546.b
- (25) Department of Clinical Genetics Helsinki University Hospital Helsinki Finland
- (26) Hereditary Cancer Clinic Prince of Wales Hospital Randwick Australia
- (27) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
- (28) University of Toronto, grid.17063.33
- (29) Laboratory of Cell Biology, Department of Pathology, hus 9, Landspitali‐LSH v/Hringbraut, 101 Reykjavik, Iceland and BMC (Biomedical Centre), Faculty of Medicine University of Iceland Reykjavik Iceland
- (30) Department of Gynaecology & Oncology Medical University of Vienna Austria
- (31) Department of Breast Medical Oncology and Clinical Cancer Genetics Program University Of Texas MD Anderson Cancer Center Houston USA
- (32) Medical University of Vienna, grid.22937.3d
- (33) Unit of Medical Genetics, Department of Medical Oncology and Hematology Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT) Milan Italy
- (34) Department of Medical Oncology Vall d'Hebron University Hospital Barcelona Spain
- (35) European Institute of Oncology, grid.15667.33
- (36) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
- (37) Human Genetics Group and Genotyping Unit (CEGEN), Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO) Madrid Spain
- (38) Dept of OB/GYN, Comprehensive Cancer Center Medical University of Vienna Vienna Austria
- (39) The Institute of Oncology Chaim Sheba Medical Center Ramat Gan Israel
- (40) University of California, San Francisco, grid.266102.1
- (41) Department of Clinical Genetics Maastricht University Medical Center Maastricht The Netherlands
- (42) Unité de Prévention et d'Epidémiologie Génétique Centre Léon Bérard, 28 rue Laënnec Lyon France
- (43) University of Pennsylvania, grid.25879.31
- (44) Department of Clinical Genetics Royal Devon & Exeter Hospital Exeter UK
- (45) Service de Génétique Institut Curie, 26 rue d'Ulm Paris France
- (46) Department of Medicine Huntsman Cancer Institute Salt Lake City USA
- (47) Molecular Oncology Laboratory Hospital Clinico San Carlos Instituto de Investigación Sanitaria San Carlos (IdISSC) Centro Investigación Biomédica en Red de Cáncer (CIBERONC) Madrid Spain
- (48) Institute of Human Genetics University Hospital of Schleswig‐Holstein Kiel Germany
- (49) Section of Molecular Genetics, Dept. of Laboratory Medicine University Hospital of Pisa Pisa Italy
- (50) Research Division Peter MacCallum Cancer Centre Melbourne Australia
- (51) CRCHU de Quebec‐oncologie, Centre des maladies du sein Deschênes‐Fabia Hôpital du Saint‐Sacrement Sainte‐Foy Canada
- (52) Columbia University, grid.21729.3f
- (53) Ghent University, grid.5342.0
- (54) Department of Clinical Genetics, Family Cancer Clinic Erasmus University Medical Center Rotterdam The Netherlands
- (55) Sheffield Clinical Genetics Service Sheffield Children's Hospital Sheffield UK
- (56) University of Glasgow, grid.8756.c
- (57) Unité d'oncogénétique ICO‐Centre René Gauducheau Saint Herblain France
- (58) Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area Vall d'Hebron University Hospital Barcelona Spain
- (59) Department of Population Sciences Beckman Research Institute of City of Hope Duarte USA
- (60) Ludwig Maximilian University of Munich, grid.5252.0
- (61) Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM Universidad de Valladolid Valladolid Spain
- (62) University of Münster, grid.5949.1
- (63) Nottingham Clinical Genetics Service Nottingham University Hospitals NHS Trust Nottingham UK
- (64) National Health Service, grid.451052.7
- (65) Skåne University Hospital, grid.411843.b
- (66) Department of Oncology, Rigshospitalet Copenhagen University Hospital Copenhagen Denmark
- (67) Institute for Medical Informatics, Statistics and Epidemiology University of Leipzig Leipzig Germany
- (68) Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar Technical University Munich Germany
- (69) Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Sciences University of Manchester, Central Manchester University Hospitals NHS Foundation Trust Manchester UK
- (70) Centre de Lutte Contre le Cancer Georges François Leclerc, France and Genomic and Immunotherapy Medical Institute Dijon University Hospital Dijon France
- (71) Molecular Diagnostic Unit, Hereditary Cancer Program, ICO‐IDIBELL (Catalan Institute of Oncology‐Bellvitge Biomedical Research Institute) Barcelona Spain
- (72) Laboratoire de Génétique Chromosomique Hôtel Dieu Centre Hospitalier Chambéry France
- (73) Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic
- (74) Columbus University, grid.441420.7
- (75) Oncogenetics Department Barretos Cancer Hospital Barretos Brazil
- (76) UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research Jonsson Comprehensive Cancer Center Los Angeles USA
- (77) Dana-Farber Cancer Institute, grid.65499.37
- (78) University of Würzburg, grid.8379.5
- (79) Department of Tumour Biology Institut Curie Paris France
- (80) Institute Curie, grid.418596.7
- (81) Department of Clinical Genetics Copenhagen Denmark
- (82) Service Régional Oncogénétique Poitou‐Charentes Centre Hospitalier Niort France
- (83) Department of Molecular Medicine University La Sapienza, and Istituto Pasteur ‐ Fondazione Cenci‐Bolognetti Rome Italy
- (84) Bâtiment Cheney D Centre Léon Bérard Lyon France
- (85) Ontario Cancer Genetics Network: Lunenfeld‐Tanenbaum Research Institute Mount Sinai Hospital Toronto Canada
- (86) Department of Pathology and Laboratory Medicine University of Kansas Medical Center Kansas City USA
- (87) Clinical Genetics Branch, DCEG, NCI NIH Bethesda USA
- (88) Pomeranian Medical University, grid.107950.a
- (89) Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty University Hospital Cologne Cologne Germany
- (90) The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Netherlands Cancer Institute Amsterdam The Netherlands
- (91) Institute of Genetic Medicine Centre for Life Newcastle Upon Tyne Hospitals NHS Trust Newcastle upon Tyne UK
- (92) Institute of Human Genetics University Leipzig Leipzig Germany
- (93) Family Cancer Clinic Netherlands Cancer Institute Amsterdam The Netherlands
- (94) Department of Gynaecology and Obstetrics University Hospital Düsseldorf, Heinrich‐Heine University Düsseldorf Germany
- (95) Institute of Oncology NN Petrov, grid.465337.0
- (96) Georgetown University, grid.213910.8
- (97) Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona) Catalan Institute of Oncology Girona Spain
- (98) Parkville Familial Cancer Centre Peter MacCallum Cancer Centre Melbourne Australia
- (99) Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine Vilnius University Hospital Santariskiu Clinics Vilnius Lithuania
- (100) Department of Clinical Genetics Aarhus University Hospital Aarhus N Denmark
- (101) Department of Epidemiology, Cancer Prevention Institute of California Fremont USA
- (102) Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute Stanford University School of Medicine Stanford USA
- (103) Clinical Genetics Research Laboratory, Dept. of Medicine Memorial Sloan‐Kettering Cancer Center New York USA
- (104) Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars‐Sinai Medical Center Los Angeles USA
- (105) Department of Gynecology and Obstetrics Medical Faculty and University Hospital Carl Gustav Carus Dresden Germany
- (106) Peter MacCallum Cancer Centre, grid.1055.1
- (107) University of Melbourne, grid.1008.9
- (108) Department of Surgery Daerim St. Mary's Hospital Seoul Korea
- (109) Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology) National Centre for Scientific Research “Demokritos” Athens Greece
- (110) The Gyneco‐Oncology Department Chaim Sheba Medical Center Ramat Gan Israel
- (111) Servicio de Genética‐CIBERER U705 Hospital de la Santa Creu i Sant Pau Barcelona Spain
- (112) Feinstein Institute for Medical Research, grid.250903.d
- (113) Soonchunhyang University, grid.412674.2
- (114) Inserm U900, Institut Curie PSL Research University Paris France
- (115) Department of Oncology Radiumhemmet and Institution of Oncology and Patology Karolinska University Hospital and Karolinska Institutet Solna Sweden
- (116) Department of Health Sciences Research Mayo Clinic Scottsdale USA
- (117) Oncogénétique Institut Bergonié Bordeaux France
- (118) Clinical Genetics Branch, DCEG, NCI, NIH Bethesda USA
- (119) Department of Gynecological Oncology and Clinical Cancer Genetics Program University Of Texas MD Anderson Cancer Center Houston USA
- (120) Centre Antoine Lacassagne, grid.417812.9
- (121) Laboratorio de Genética Molecular, Servicio de Genética Hospital Universitario Cruces, BioCruces Health Research Institute Barakaldo Spain
- (122) Department of Clinical Genetics VU University Medical Center Amsterdam The Netherlands
- (123) Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands
- (124) Vilnius University, grid.6441.7
- (125) NRG Oncology Statistics and Data Management Center Roswell Park Cancer Institute Buffalo USA
- (126) Department of Cancer Prevention and Control Roswell Park Cancer Institute Buffalo USA
- (127) Department of Obstetrics and Gynecology University of Helsinki and Helsinki University Hospital HUS Finland
- (128) Cancer Genetics Service Division of Medical Oncology National Cancer Centre Singapore Bukit Merah Singapore
- (129) University of Tübingen, grid.10392.39
- (130) Rigshospitalet, grid.475435.4, Capital Region
- (131) Clinical Genetics Research Laboratory Dept. of Medicine Cancer Biology and Genetics Memorial Sloan‐Kettering Cancer Center New York USA
- (132) Department of Clinical Genetics Sahlgrenska University Hospital Gothenburg Sweden
- (133) West Midlands Regional Genetics Service Birmingham Women's Hospital Healthcare NHS Trust Edgbaston UK
- (134) Spanish National Cancer Research Centre, grid.7719.8
- (135) University of Florence, grid.8404.8
- (136) University of Turin, grid.7605.4
- (137) Section of Molecular Diagnostics Department of Biochemistry Aalborg University Hospital Aalborg Denmark
- (138) Department of Genetics Portuguese Oncology Institute of Porto (IPO Porto) Porto Portugal
- (139) University of Porto, grid.5808.5
- (140) IFOM The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology Milan Italy
- (141) Service de Génétique Clinique Chromosomique et Moléculaire Hôpital Nord St Etienne France
- (142) Unité d'Oncogénétique CHU Arnaud de Villeneuve Montpellier France
- (143) Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Istituto Nazionale Tumori (INT) Milan Italy
- (144) The Kinghorn Cancer Centre, grid.410697.d
- (145) UNSW Sydney, grid.1005.4
- (146) Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden
- (147) Department of Basic Sciences Shaukat Khanum Memorial Cancer Hospital and Research Centre Lahore Pakistan
- (148) Clinical Genetics Services Dept. of Medicine Memorial Sloan‐Kettering Cancer Center New York USA
- (149) Division of Gynecologic Oncology North Shore University Health System University of Chicago Evanston USA
- (150) All Wales Medical Genetics Services University Hospital of Wales Cardiff UK
- (151) Department of Gynecology Vilnius University Hospital Santariskiu Clinics Centre of Woman's Health and pathology Vilnius Lithuania
- (152) Clinical Cancer Genetics Program Division of Human Genetics Department of Internal Medicine The Comprehensive Cancer Center The Ohio State University Columbus USA
- (153) Department of Internal Medicine Division of Oncology University of Kansas Medical Center Westwood USA
- (154) Genomics Center Centre Hospitalier Universitaire de Québec Research Center and Laval University Quebec City Canada
- (155) Medical Genetics Unit University of London St George's UK
- (156) Département Oncologie Génétique Prévention et Dépistage Institut Paoli‐Calmettes Marseille Medical School‐AM University Marseille France
- (157) Institute of Cell and Molecular Pathology Hannover Medical School Hannover Germany
- (158) University Hospital Heidelberg, grid.5253.1
- (159) National Human Genome Research Institute, grid.280128.1
- (160) Genetic Counseling Unit Hereditary Cancer Program IDIBELL (Bellvitge Biomedical Research Institute) Catalan Institute of Oncology, CIBERONC Gran Via de l'Hospitalet Barcelona Spain
- (161) Mayo Clinic, grid.66875.3a
- (162) Department of Medicine Magee‐Womens Hospital University of Pittsburgh School of Medicine Pittsburgh USA
- (163) Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montreal Canada
- (164) Division of Human Genetics Departments of Internal Medicine and Cancer Biology and Genetics Comprehensive Cancer Center The Ohio State University Columbus USA
- (165) Parkville Familial Cancer Centre Royal Melbourne Hospital Melbourne Australia
- (166) Department of Medical Oncology Beth Israel Deaconess Medical Center Massachusetts USA
- (167) Leiden University Medical Center, grid.10419.3d
- (168) Department of Genetics University Medical Center Groningen University Groningen The Netherlands
- (169) University Medical Center Utrecht, grid.7692.a
- (170) Unit of Hereditary Cancer Department of Epidemiology, Prevention and Special Functions IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) AOU San Martino ‐ IST Istituto Nazionale per la Ricerca sul Cancro Genoa Italy
- (171) Institute of Human Genetics Campus Virchov Klinikum Berlin Germany
- (172) Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela Spain
- (173) Centro de Cancer de Mama del Hospital Zambrano Hellion Tecnologico de Monterrey San Pedro Garza Garcia Mexico
- (174) Departamento de Investigacion y de Tumores Mamarios del Instituto Nacional de Cancerologia Mexico City Mexico
- (175) Karolinska University Hospital, grid.24381.3c
- (176) Oxford Regional Genetics Service Churchill Hospital Oxford UK
- (177) Department of Gynaecology and Obstetrics University Hospital Ulm Germany
- (178) University of Regensburg, grid.7727.5
- (179) Institute of Oncology Rivka Ziv Medical Center Zefat Israel
- (180) Magee-Womens Hospital, grid.411487.f
- (181) Center for Medical Genetics North Shore University Health System Evanston USA
- (182) Medical Director, Center for Medical Genetics, NorthShore University HealthSystem, Clinical Assistant Professor of Medicine University of Chicago Pritzker School of Medicine Evanston USA
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Description
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.