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 RB37, Barrowdale D20, Benitez J38,39, Berger A40, Berger R41, Blanco AM42, Blazer KR10, Blok MJ43, Bonadona V44, Bonanni B36, Bradbury AR45, Brewer C46, Buecher B47, Buys SS48, Caldes T49, Caliebe A50, Caligo MA51, Campbell I52, Caputo S47, Chiquette J53, Chung WK54, Claes KBM55, Collée JM56, Cook J57, Davidson R58, de la Hoya M49, De Leeneer K55, de Pauw A47, Delnatte C59, Diez O60, Ding YC61, Ditsch N62, Domchek SM45, Dorfling CM19, Velazquez C63, Dworniczak B64, Eason J65, Easton DF20, Eeles R66, Ehrencrona H67, Ejlertsen B68; EMBRACE20, Engel C69, Engert S70, Evans DG71, Faivre L72, Feliubadaló L73, Ferrer SF74, Foretova L75, Fowler J76, Frost D20, Galvão HCR77, Ganz PA78, Garber J79, Gauthier-Villars M47, Gehrig A80; GEMO Study Collaborators81,82, Gerdes AM83, Gesta P84, Giannini G85, Giraud S86, Glendon G87, Godwin AK88, Greene MH89, Gronwald J90, Gutierrez-Barrera A32, Hahnen E91, Hauke J91; HEBON92, Henderson A93, Hentschel J94, Hogervorst FBL95, Honisch E96, Imyanitov EN97, Isaacs C98, Izatt L99, Izquierdo A100, Jakubowska A90, James P101, Janavicius R102, Jensen UB103, John EM104,105, Joseph V106, Kaczmarek K90, Karlan BY107, Kast K108, Investigators K109, Kim SW110, Konstantopoulou I111, Korach J112, Laitman Y2, Lasa A113, Lasset C44, Lázaro C73, Lee A114, Lee MH115, Lester J107, Lesueur F116, Liljegren A117, Lindor NM118, Longy M119, Loud JT120, Lu KH121, Lubinski J90, Machackova E75, Manoukian S34, Mari V122, Martínez-Bouzas C123, Matrai Z124, Mebirouk N116, Meijers-Heijboer HEJ125, Meindl A70, Mensenkamp AR126, Mickys U127, Miller A128, Montagna M25, Moysich KB129, Mulligan AM130, Musinsky J106, Neuhausen SL61, Nevanlinna H131, Ngeow J132, Nguyen HP133, Niederacher D96, Nielsen HR9, Nielsen FC134, Nussbaum RL135, Offit K136, Öfverholm A137, Ong KR138, Osorio A139, Papi L140, Papp J6, Pasini B141, Pedersen IS142, MSc AP143,144, MSc NP90, Peterlongo P145, Pohl E91, Ba NP106, Prajzendanc K90, Prieur F146, Pujol P147, Radice P148, Ramus SJ149,150, Rantala J151, Rashid MU3,152, Rhiem K91, Robson M153, Rodriguez GC154, Rogers MT155, Rudaitis V156, Schmidt AY134, Schmutzler RK91, Senter L157, Shah PD45, Sharma P158, Side LE159, Simard J160, Singer CF33, Skytte AB103, Slavin TP10, Snape K161, Sobol H162, Southey M162,163, Steele L61, Steinemann D164, Sukiennicki G90, Sutter C165, Szabo CI166, Tan YY40, Teixeira MR143,144, Terry MB167, Teulé A168, Thomas A169, Thull DL170, Tischkowitz M171, Tognazzo S25, Toland AE172, Topka S106, Trainer AH173, Tung N174, van Asperen CJ175, van der Hout AH176, van der Kolk LE177, van der Luijt RB178, Van Heetvelde M55, Varesco L179, Varon-Mateeva R180, Vega A181, Villarreal-Garza C182,183, von Wachenfeldt A184, Walker L185, Wang-Gohrke S186, Wappenschmidt B90, Weber BHF187, Yannoukakos D111, Yoon SY8, Zanzottera C34, Zidan J188, Zorn KK189, Selkirk CGH190, Hulick PJ191, Chenevix-Trench G21, Spurdle AB21, Antoniou AC20, Nathanson KL45; CIMBA Consortium1.

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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 Caucasians 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 6 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. This article is protected by copyright. All rights reserved.