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. 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

Timothy R Rebbeck  1 , Tara M Friebel  1 , Eitan Friedman  2 , Ute Hamann  3 , Dezheng Huo  4 , Ava Kwong  5 , Edith Olah  6 , Olufunmilayo I Olopade  4 , Angela R Solano  7 , Soo-Hwang Teo  8 , Mads Thomassen  9 , Jeffrey N Weitzel  10 , T L Chan  11 , Fergus J Couch  12 , David E Goldgar  13 , Torben A Kruse  9 , Edenir Inêz Palmero  14 , Sue Kyung Park  15   16   17 , Diana Torres  3   18 , Elizabeth J van Rensburg  19 , Lesley McGuffog  20 , Michael T Parsons  21 , Goska Leslie  20 , Cora M Aalfs  22 , Julio Abugattas  23 , Julian Adlard  24 , Simona Agata  25 , Kristiina Aittomäki  26 , Lesley Andrews  27 , Irene L Andrulis  28   29 , Adalgeir Arason  30 , Norbert Arnold  31 , Banu K Arun  32 , Ella Asseryanis  33 , Leo Auerbach  33 , Jacopo Azzollini  34 , Judith Balmaña  35 , Monica Barile  36 , Rosa B Barkardottir  30 , Daniel Barrowdale  20 , Javier Benitez  37   38 , Andreas Berger  39 , Raanan Berger  40 , Amie M Blanco  41 , Kathleen R Blazer  10 , Marinus J Blok  42 , Valérie Bonadona  43 , Bernardo Bonanni  36 , Angela R Bradbury  44 , Carole Brewer  45 , Bruno Buecher  46 , Saundra S Buys  47 , Trinidad Caldes  48 , Almuth Caliebe  49 , Maria A Caligo  50 , Ian Campbell  51 , Sandrine M Caputo  46 , Jocelyne Chiquette  52 , Wendy K Chung  53 , Kathleen B M Claes  54 , J Margriet Collée  55 , Jackie Cook  56 , Rosemarie Davidson  57 , Miguel de la Hoya  48 , Kim De Leeneer  54 , Antoine de Pauw  46 , Capucine Delnatte  58 , Orland Diez  59 , Yuan Chun Ding  60 , Nina Ditsch  61 , Susan M Domchek  44 , Cecilia M Dorfling  19 , Carolina Velazquez  62 , Bernd Dworniczak  63 , Jacqueline Eason  64 , Douglas F Easton  20 , Ros Eeles  65 , Hans Ehrencrona  66 , Bent Ejlertsen  67 ; EMBRACE  20 ; Christoph Engel  68 , Stefanie Engert  69 , D Gareth Evans  70 , Laurence Faivre  71 , Lidia Feliubadaló  72 , Sandra Fert Ferrer  73 , Lenka Foretova  74 , Jeffrey Fowler  75 , Debra Frost  20 , Henrique C R Galvão  76 , Patricia A Ganz  77 , Judy Garber  78 , Marion Gauthier-Villars  46 , Andrea Gehrig  79 ; GEMO Study Collaborators  80   81 ; Anne-Marie Gerdes  82 , Paul Gesta  83 , Giuseppe Giannini  84 , Sophie Giraud  85 , Gord Glendon  86 , Andrew K Godwin  87 , Mark H Greene  88 , Jacek Gronwald  89 , Angelica Gutierrez-Barrera  32 , Eric Hahnen  90 , Jan Hauke  90 ; HEBON  91 ; Alex Henderson  92 , Julia Hentschel  93 , Frans B L Hogervorst  94 , Ellen Honisch  95 , Evgeny N Imyanitov  96 , Claudine Isaacs  97 , Louise Izatt  98 , Angel Izquierdo  99 , Anna Jakubowska  89 , Paul James  100 , Ramunas Janavicius  101 , Uffe Birk Jensen  102 , Esther M John  103   104 , Joseph Vijai  105 , Katarzyna Kaczmarek  89 , Beth Y Karlan  106 , Karin Kast  107 , KConFab Investigators  108 , Sung-Won Kim  109 , Irene Konstantopoulou  110 , Jacob Korach  111 , Yael Laitman  2 , Adriana Lasa  112 , Christine Lasset  43 , Conxi Lázaro  72 , Annette Lee  113 , Min Hyuk Lee  114 , Jenny Lester  106 , Fabienne Lesueur  115 , Annelie Liljegren  116 , Noralane M Lindor  117 , Michel Longy  118 , Jennifer T Loud  88 , Karen H Lu  119 , Jan Lubinski  89 , Eva Machackova  74 , Siranoush Manoukian  34 , Véronique Mari  120 , Cristina Martínez-Bouzas  121 , Zoltan Matrai  122 , Noura Mebirouk  115 , Hanne E J Meijers-Heijboer  123 , Alfons Meindl  69 , Arjen R Mensenkamp  124 , Ugnius Mickys  125 , Austin Miller  126 , Marco Montagna  25 , Kirsten B Moysich  127 , Anna Marie Mulligan  128 , Jacob Musinsky  105 , Susan L Neuhausen  60 , Heli Nevanlinna  129 , Joanne Ngeow  130 , Huu Phuc Nguyen  131 , Dieter Niederacher  95 , Henriette Roed Nielsen  9 , Finn Cilius Nielsen  132 , Robert L Nussbaum  133 , Kenneth Offit  134 , Anna Öfverholm  135 , Kai-Ren Ong  136 , Ana Osorio  137 , Laura Papi  138 , Janos Papp  6 , Barbara Pasini  139 , Inge Sokilde Pedersen  140 , Ana Peixoto  141   142 , Nina Peruga  89 , Paolo Peterlongo  143 , Esther Pohl  90 , Nisha Pradhan  105 , Karolina Prajzendanc  89 , Fabienne Prieur  144 , Pascal Pujol  145 , Paolo Radice  146 , Susan J Ramus  147   148 , Johanna Rantala  149 , Muhammad Usman Rashid  3   150 , Kerstin Rhiem  90 , Mark Robson  151 , Gustavo C Rodriguez  152 , Mark T Rogers  153 , Vilius Rudaitis  154 , Ane Y Schmidt  132 , Rita Katharina Schmutzler  90 , Leigha Senter  155 , Payal D Shah  44 , Priyanka Sharma  156 , Lucy E Side  157 , Jacques Simard  158 , Christian F Singer  33 , Anne-Bine Skytte  102 , Thomas P Slavin  10 , Katie Snape  159 , Hagay Sobol  160 , Melissa Southey  160   161 , Linda Steele  60 , Doris Steinemann  162 , Grzegorz Sukiennicki  89 , Christian Sutter  163 , Csilla I Szabo  164 , Yen Y Tan  39 , Manuel R Teixeira  141   142 , Mary Beth Terry  165 , Alex Teulé  166 , Abigail Thomas  167 , Darcy L Thull  168 , Marc Tischkowitz  169 , Silvia Tognazzo  25 , Amanda Ewart Toland  170 , Sabine Topka  105 , Alison H Trainer  171 , Nadine Tung  172 , Christi J van Asperen  173 , Annemieke H van der Hout  174 , Lizet E van der Kolk  94 , Rob B van der Luijt  175 , Mattias Van Heetvelde  54 , Liliana Varesco  176 , Raymonda Varon-Mateeva  177 , Ana Vega  178 , Cynthia Villarreal-Garza  179   180 , Anna von Wachenfeldt  181 , Lisa Walker  182 , Shan Wang-Gohrke  183 , Barbara Wappenschmidt  90 , Bernhard H F Weber  184 , Drakoulis Yannoukakos  110 , Sook-Yee Yoon  8 , Cristina Zanzottera  34 , Jamal Zidan  185 , Kristin K Zorn  186 , Christina G Hutten Selkirk  187 , Peter J Hulick  188 , Georgia Chenevix-Trench  21 , Amanda B Spurdle  21 , Antonis C Antoniou  20 , Katherine L Nathanson  44
Affiliations

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

Timothy R Rebbeck et al. Hum Mutat. 2018 May.

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.

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