Dataset Information

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

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.

SUBMITTER: Rebbeck TR

PROVIDER: S-EPMC5903938 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Rebbeck Timothy R TR Friebel Tara M TM Friedman Eitan E Hamann Ute U Huo Dezheng D Kwong Ava A Olah Edith E Olopade Olufunmilayo I OI Solano Angela R AR Teo Soo-Hwang SH Thomassen Mads M Weitzel Jeffrey N JN Chan T L TL Couch Fergus J FJ Goldgar David E DE Kruse Torben A TA Palmero Edenir Inêz EI Park Sue Kyung SK Torres Diana D van Rensburg Elizabeth J EJ McGuffog Lesley L Parsons Michael T MT Leslie Goska G Aalfs Cora M CM Abugattas Julio J Adlard Julian J Agata Simona S Aittomäki Kristiina K Andrews Lesley L Andrulis Irene L IL Arason Adalgeir A Arnold Norbert N Arun Banu K BK Asseryanis Ella E Auerbach Leo L Azzollini Jacopo J Balmaña Judith J Barile Monica M Barkardottir Rosa B RB Barrowdale Daniel D Benitez Javier J Berger Andreas A Berger Raanan R Blanco Amie M AM Blazer Kathleen R KR Blok Marinus J MJ Bonadona Valérie V Bonanni Bernardo B Bradbury Angela R AR Brewer Carole C Buecher Bruno B Buys Saundra S SS Caldes Trinidad T Caliebe Almuth A Caligo Maria A MA Campbell Ian I Caputo Sandrine M SM Chiquette Jocelyne J Chung Wendy K WK Claes Kathleen B M KBM Collée J Margriet JM Cook Jackie J Davidson Rosemarie R de la Hoya Miguel M De Leeneer Kim K de Pauw Antoine A Delnatte Capucine C Diez Orland O Ding Yuan Chun YC Ditsch Nina N Domchek Susan M SM Dorfling Cecilia M CM Velazquez Carolina C Dworniczak Bernd B Eason Jacqueline J Easton Douglas F DF Eeles Ros R Ehrencrona Hans H Ejlertsen Bent B Engel Christoph C Engert Stefanie S Evans D Gareth DG Faivre Laurence L Feliubadaló Lidia L Ferrer Sandra Fert SF Foretova Lenka L Fowler Jeffrey J Frost Debra D Galvão Henrique C R HCR Ganz Patricia A PA Garber Judy J Gauthier-Villars Marion M Gehrig Andrea A Gerdes Anne-Marie AM Gesta Paul P Giannini Giuseppe G Giraud Sophie S Glendon Gord G Godwin Andrew K AK Greene Mark H MH Gronwald Jacek J Gutierrez-Barrera Angelica A Hahnen Eric E Hauke Jan J Henderson Alex A Hentschel Julia J Hogervorst Frans B L FBL Honisch Ellen E Imyanitov Evgeny N EN Isaacs Claudine C Izatt Louise L Izquierdo Angel A Jakubowska Anna A James Paul P Janavicius Ramunas R Jensen Uffe Birk UB John Esther M EM Vijai Joseph J Kaczmarek Katarzyna K Karlan Beth Y BY Kast Karin K Investigators KConFab K Kim Sung-Won SW Konstantopoulou Irene I Korach Jacob J Laitman Yael Y Lasa Adriana A Lasset Christine C Lázaro Conxi C Lee Annette A Lee Min Hyuk MH Lester Jenny J Lesueur Fabienne F Liljegren Annelie A Lindor Noralane M NM Longy Michel M Loud Jennifer T JT Lu Karen H KH Lubinski Jan J Machackova Eva E Manoukian Siranoush S Mari Véronique V Martínez-Bouzas Cristina C Matrai Zoltan Z Mebirouk Noura N Meijers-Heijboer Hanne E J HEJ Meindl Alfons A Mensenkamp Arjen R AR Mickys Ugnius U Miller Austin A Montagna Marco M Moysich Kirsten B KB Mulligan Anna Marie AM Musinsky Jacob J Neuhausen Susan L SL Nevanlinna Heli H Ngeow Joanne J Nguyen Huu Phuc HP Niederacher Dieter D Nielsen Henriette Roed HR Nielsen Finn Cilius FC Nussbaum Robert L RL Offit Kenneth K Öfverholm Anna A Ong Kai-Ren KR Osorio Ana A Papi Laura L Papp Janos J Pasini Barbara B Pedersen Inge Sokilde IS Peixoto Ana A Peruga Nina N Peterlongo Paolo P Pohl Esther E Pradhan Nisha N Prajzendanc Karolina K Prieur Fabienne F Pujol Pascal P Radice Paolo P Ramus Susan J SJ Rantala Johanna J Rashid Muhammad Usman MU Rhiem Kerstin K Robson Mark M Rodriguez Gustavo C GC Rogers Mark T MT Rudaitis Vilius V Schmidt Ane Y AY Schmutzler Rita Katharina RK Senter Leigha L Shah Payal D PD Sharma Priyanka P Side Lucy E LE Simard Jacques J Singer Christian F CF Skytte Anne-Bine AB Slavin Thomas P TP Snape Katie K Sobol Hagay H Southey Melissa M Steele Linda L Steinemann Doris D Sukiennicki Grzegorz G Sutter Christian C Szabo Csilla I CI Tan Yen Y YY Teixeira Manuel R MR Terry Mary Beth MB Teulé Alex A Thomas Abigail A Thull Darcy L DL Tischkowitz Marc M Tognazzo Silvia S Toland Amanda Ewart AE Topka Sabine S Trainer Alison H AH Tung Nadine N van Asperen Christi J CJ van der Hout Annemieke H AH van der Kolk Lizet E LE van der Luijt Rob B RB Van Heetvelde Mattias M Varesco Liliana L Varon-Mateeva Raymonda R Vega Ana A Villarreal-Garza Cynthia C von Wachenfeldt Anna A Walker Lisa L Wang-Gohrke Shan S Wappenschmidt Barbara B Weber Bernhard H F BHF Yannoukakos Drakoulis D Yoon Sook-Yee SY Zanzottera Cristina C Zidan Jamal J Zorn Kristin K KK Hutten Selkirk Christina G CG Hulick Peter J PJ Chenevix-Trench Georgia G Spurdle Amanda B AB Antoniou Antonis C AC Nathanson Katherine L KL

Human mutation 20180312 5

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 ...[more]

PMID: 29446198

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Project description:BACKGROUND: The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain). METHODS: In the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: A total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family. CONCLUSIONS: In this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area.

Dataset Information

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

Publications

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

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