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Hum Mutat. 2018 May;39(5):593-620. doi: 10.1002/humu.23406. Epub 2018 Mar 12.

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Rebbeck TR1, Friebel TM1, Friedman E2, Hamann U3, Huo D4, Kwong A5, Olah E6, Olopade OI4, Solano AR7, Teo SH8, Thomassen M9, Weitzel JN10, Chan TL11, Couch FJ12, Goldgar DE13, Kruse TA9, Palmero EI14, Park SK15,16,17, Torres D3,18, van Rensburg EJ19, McGuffog L20, Parsons MT21, Leslie G20, Aalfs CM22, Abugattas J23, Adlard J24, Agata S25, Aittomäki K26, Andrews L27, Andrulis IL28,29, Arason A30, Arnold N31, Arun BK32, Asseryanis E33, Auerbach L33, Azzollini J34, Balmaña J35, Barile M36, Barkardottir RB30, Barrowdale D20, Benitez J37,38, Berger A39, Berger R40, Blanco AM41, Blazer KR10, Blok MJ42, Bonadona V43, Bonanni B36, Bradbury AR44, Brewer C45, Buecher B46, Buys SS47, Caldes T48, Caliebe A49, Caligo MA50, Campbell I51, Caputo SM46, Chiquette J52, Chung WK53, Claes KBM54, Collée JM55, Cook J56, Davidson R57, de la Hoya M48, De Leeneer K54, de Pauw A46, Delnatte C58, Diez O59, Ding YC60, Ditsch N61, Domchek SM44, Dorfling CM19, Velazquez C62, Dworniczak B63, Eason J64, Easton DF20, Eeles R65, Ehrencrona H66, Ejlertsen B67; EMBRACE20, Engel C68, Engert S69, Evans DG70, Faivre L71, Feliubadaló L72, Ferrer SF73, Foretova L74, Fowler J75, Frost D20, Galvão HCR76, Ganz PA77, Garber J78, Gauthier-Villars M46, Gehrig A79; GEMO Study Collaborators80,81, Gerdes AM82, Gesta P83, Giannini G84, Giraud S85, Glendon G86, Godwin AK87, Greene MH88, Gronwald J89, Gutierrez-Barrera A32, Hahnen E90, Hauke J90; HEBON91, Henderson A92, Hentschel J93, Hogervorst FBL94, Honisch E95, Imyanitov EN96, Isaacs C97, Izatt L98, Izquierdo A99, Jakubowska A89, James P100, Janavicius R101, Jensen UB102, John EM103,104, Vijai J105, Kaczmarek K89, Karlan BY106, Kast K107, Investigators K108, Kim SW109, Konstantopoulou I110, Korach J111, Laitman Y2, Lasa A112, Lasset C43, Lázaro C72, Lee A113, Lee MH114, Lester J106, Lesueur F115, Liljegren A116, Lindor NM117, Longy M118, Loud JT88, Lu KH119, Lubinski J89, Machackova E74, Manoukian S34, Mari V120, Martínez-Bouzas C121, Matrai Z122, Mebirouk N115, Meijers-Heijboer HEJ123, Meindl A69, Mensenkamp AR124, Mickys U125, Miller A126, Montagna M25, Moysich KB127, Mulligan AM128, Musinsky J105, Neuhausen SL60, Nevanlinna H129, Ngeow J130, Nguyen HP131, Niederacher D95, Nielsen HR9, Nielsen FC132, Nussbaum RL133, Offit K134, Öfverholm A135, Ong KR136, Osorio A137, Papi L138, Papp J6, Pasini B139, Pedersen IS140, Peixoto A141,142, Peruga N89, Peterlongo P143, Pohl E90, Pradhan N105, Prajzendanc K89, Prieur F144, Pujol P145, Radice P146, Ramus SJ147,148, Rantala J149, Rashid MU3,150, Rhiem K90, Robson M151, Rodriguez GC152, Rogers MT153, Rudaitis V154, Schmidt AY132, Schmutzler RK90, Senter L155, Shah PD44, Sharma P156, Side LE157, Simard J158, Singer CF33, Skytte AB102, Slavin TP10, Snape K159, Sobol H160, Southey M160,161, Steele L60, Steinemann D162, Sukiennicki G89, Sutter C163, Szabo CI164, Tan YY39, Teixeira MR141,142, Terry MB165, Teulé A166, Thomas A167, Thull DL168, Tischkowitz M169, Tognazzo S25, Toland AE170, Topka S105, Trainer AH171, Tung N172, van Asperen CJ173, van der Hout AH174, van der Kolk LE94, van der Luijt RB175, Van Heetvelde M54, Varesco L176, Varon-Mateeva R177, Vega A178, Villarreal-Garza C179,180, von Wachenfeldt A181, Walker L182, Wang-Gohrke S183, Wappenschmidt B90, Weber BHF184, Yannoukakos D110, Yoon SY8, Zanzottera C34, Zidan J185, Zorn KK186, Hutten Selkirk CG187, Hulick PJ188, Chenevix-Trench G21, Spurdle AB21, Antoniou AC20, Nathanson KL44.

Author information

1
Harvard TH Chan School of Public Health and Dana Farber Cancer Institute, Boston, USA.
2
The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan 52621, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
3
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
7
INBIOMED, Faculty of Medicine, University of Buenos Aires/CONICET and CEMIC, Department of Clinical Chemistry, Medical Direction, Buenos Aires, Argentina.
8
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.
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
Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea.
17
Cancer Research Center, Seoul National University, Seoul, Korea.
18
Institute of Human Genetics, Pontificia Universidad Javeriana, Colombia.
19
Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, South Africa.
20
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
21
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
22
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
23
City of Hope Clinical Cancer Genomics Community Research Network, Duarte, USA.
24
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.
25
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
26
Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland.
27
Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Australia.
28
Lunenfeld-Tanenbaum Research Institute, Toronto, Canada.
29
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
30
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.
31
Department of Gynaecology & Oncology, Medical University of Vienna, Austria.
32
Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, Houston, USA.
33
Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
34
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.
35
Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
36
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy.
37
Human Genetics Group and Genotyping Unit (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
38
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
39
Dept of OB/GYN, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
40
The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel.
41
UCSF Cancer Genetics and Prevention Program, San Francisco, USA.
42
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
43
Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, Lyon, France.
44
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.
45
Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK.
46
Service de Génétique, Institut Curie, 26 rue d'Ulm, Paris, France.
47
Department of Medicine, Huntsman Cancer Institute, Salt Lake City, USA.
48
Molecular Oncology Laboratory, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
49
Institute of Human Genetics, University Hospital of Schleswig-Holstein, Kiel, Germany.
50
Section of Molecular Genetics, Dept. of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
51
Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
52
CRCHU de Quebec-oncologie, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Sainte-Foy, Canada.
53
Departments of Pediatrics and Medicine, Columbia University, New York, USA.
54
Center for Medical Genetics, Ghent University, Gent, Belgium.
55
Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
56
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
57
Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, UK.
58
Unité d'oncogénétique, ICO-Centre René Gauducheau, Saint Herblain, France.
59
Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area, Vall d'Hebron University Hospital, Barcelona, Spain.
60
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, USA.
61
Department of Gynaecology and Obstetrics, Ludwig-Maximilian University, Munich, Germany.
62
Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM, Universidad de Valladolid, Valladolid, Spain.
63
Institute of Human Genetics, University of Münster, Münster, Germany.
64
Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
65
Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
66
Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
67
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
68
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
69
Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University, Munich, Germany.
70
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.
71
Centre de Lutte Contre le Cancer Georges François Leclerc, France and Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France.
72
Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Catalan Institute of Oncology-Bellvitge Biomedical Research Institute), Barcelona, Spain.
73
Laboratoire de Génétique Chromosomique, Hôtel Dieu Centre Hospitalier, Chambéry, France.
74
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
75
Columbus Cancer Council, Ohio State University, Columbus, USA.
76
Oncogenetics Department, Barretos Cancer Hospital, Barretos, Brazil.
77
UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, USA.
78
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, USA.
79
Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University of Würzburg, Germany, Würzburg.
80
Department of Tumour Biology, Institut Curie, Paris, France.
81
Institut Curie, Paris, France.
82
Department of Clinical Genetics, Copenhagen, Denmark.
83
Service Régional Oncogénétique Poitou-Charentes, Centre Hospitalier, Niort, France.
84
Department of Molecular Medicine, University La Sapienza, and Istituto Pasteur - Fondazione Cenci-Bolognetti, Rome, Italy.
85
Bâtiment Cheney D, Centre Léon Bérard, Lyon, France.
86
Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
87
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA.
88
Clinical Genetics Branch, DCEG, NCI, NIH, Bethesda, USA.
89
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
90
Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
91
The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Netherlands Cancer Institute, Amsterdam, The Netherlands.
92
Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
93
Institute of Human Genetics, University Leipzig, Leipzig, Germany.
94
Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
95
Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany.
96
N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
97
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, USA.
98
Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
99
Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, Girona, Spain.
100
Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Australia.
101
Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania.
102
Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
103
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, USA.
104
Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, USA.
105
Clinical Genetics Research Laboratory, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA.
106
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
107
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Dresden, Germany.
108
Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia and The Sir Peter MacCallum Department of Oncology University of Melbourne, Parkville, Australia.
109
Department of Surgery, Daerim St. Mary's Hospital, Seoul, Korea.
110
Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology), National Centre for Scientific Research "Demokritos", Athens, Greece.
111
The Gyneco-Oncology Department, Chaim Sheba Medical Center, Ramat Gan, Israel.
112
Servicio de Genética-CIBERER U705, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
113
The Feinstein Institute for Medical Research, Manhasset, USA.
114
Department of Surgery, Soonchunhyang University and Seoul Hospital, Seoul, Korea.
115
Inserm U900, Institut Curie, PSL Research University, Paris, France.
116
Department of Oncology Radiumhemmet and Institution of Oncology and Patology, Karolinska University Hospital and Karolinska Institutet, Solna, Sweden.
117
Department of Health Sciences Research, Mayo Clinic, Scottsdale, USA.
118
Oncogénétique, Institut Bergonié, Bordeaux, France.
119
Department of Gynecological Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, Houston, USA.
120
Centre Antoine Lacassagne, Nice, France.
121
Laboratorio de Genética Molecular, Servicio de Genética, Hospital Universitario Cruces, BioCruces Health Research Institute, Barakaldo, Spain.
122
Department of Surgery, National Institute of Oncology, Budapest, Hungary.
123
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
124
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
125
Vilnius university Santariskiu hospital, National Center of Pathology, Vilnius, Lithuania.
126
NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, USA.
127
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, USA.
128
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
129
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, HUS, Finland.
130
Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Bukit Merah, Singapore.
131
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
132
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
133
Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, USA.
134
Clinical Genetics Research Laboratory, Dept. of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, USA.
135
Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
136
West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, UK.
137
Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
138
Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
139
Department of Medical Sciences, University of Turin, Turin, Italy.
140
Section of Molecular Diagnostics, Department of Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
141
Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
142
Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
143
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
144
Service de Génétique Clinique Chromosomique et Moléculaire, Hôpital Nord, St Etienne, France.
145
Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France.
146
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.
147
School of Women's and Children's Health, UNSW, Sydney, Australia.
148
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
149
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
150
Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan.
151
Clinical Genetics Services, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA.
152
Division of Gynecologic Oncology, North Shore University Health System, University of Chicago, Evanston, USA.
153
All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK.
154
Department of Gynecology, Vilnius University Hospital Santariskiu Clinics, Centre of Woman's Health and pathology, Vilnius, Lithuania.
155
Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
156
Department of Internal Medicine, Division of Oncology, University of Kansas Medical Center, Westwood, USA.
157
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
158
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Canada.
159
Medical Genetics Unit, University of London, St George's, UK.
160
Département Oncologie Génétique, Prévention et Dépistage, Institut Paoli-Calmettes, Marseille Medical School-AM University, Marseille, France.
161
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia.
162
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
163
Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
164
National Human Genome Research Institute, National Institutes of Health, Bethesda, USA.
165
Department of Epidemiology, Columbia University, New York, USA.
166
Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Gran Via de l'Hospitalet, Barcelona, Spain.
167
Department of Health Sciences Research, Mayo Clinic, Rochester, USA.
168
Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, USA.
169
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Canada.
170
Division of Human Genetics, Departments of Internal Medicine and Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
171
Parkville Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Australia.
172
Department of Medical Oncology, Beth Israel Deaconess Medical Center, Massachusetts, USA.
173
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
174
Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands.
175
Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands.
176
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.
177
Institute of Human Genetics, Campus Virchov Klinikum, Berlin, Germany.
178
Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.
179
Departamento de Investigacion y de Tumores Mamarios del, Instituto Nacional de Cancerologia, Mexico City, Mexico.
180
Centro de Cancer de Mama del Hospital Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza Garcia, Mexico.
181
Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
182
Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK.
183
Department of Gynaecology and Obstetrics, University Hospital, Ulm, Germany.
184
Institute of Human Genetics, Regensburg University, Regensburg, Germany.
185
Institute of Oncology, Rivka Ziv Medical Center, Zefat, Israel.
186
Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, USA.
187
Center for Medical Genetics, North Shore University Health System, Evanston, USA.
188
Medical Director, Center for Medical Genetics, NorthShore University HealthSystem, Clinical Assistant Professor of Medicine, University of Chicago Pritzker School of Medicine, Evanston, USA.

Abstract

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.

KEYWORDS:

BRCA1; BRCA2; breast cancer; ethnicity; geography; mutation; ovarian cancer

PMID:
29446198
PMCID:
PMC5903938
DOI:
10.1002/humu.23406
[Indexed for MEDLINE]
Free PMC Article

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