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.
| Original language | English |
|---|---|
| Pages (from-to) | 593-620 |
| Number of pages | 28 |
| Journal | Human Mutation |
| Volume | 39 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 May 2018 |
| Externally published | Yes |
Keywords
- BRCA1
- BRCA2
- breast cancer
- ethnicity
- geography
- mutation
- ovarian cancer
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Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. / Rebbeck, Timothy R.; Friebel, Tara M.; Friedman, Eitan; Hamann, Ute; Huo, Dezheng; Kwong, Ava; Olah, Edith; Olopade, Olufunmilayo I.; Solano, Angela R.; Teo, Soo Hwang; Thomassen, Mads; Weitzel, Jeffrey N.; Chan, T. L.; Couch, Fergus J.; Goldgar, David E.; Kruse, Torben A.; Palmero, Edenir Inêz; Park, Sue Kyung; Torres, Diana; McGuffog, Lesley; van Rensburg, Elizabeth J.; Parsons, Michael T.; Leslie, Goska; Aalfs, Cora M.; Abugattas, Julio; Adlard, Julian; Agata, Simona; Aittomäki, Kristiina; Andrews, Lesley; Andrulis, Irene L.; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K.; Asseryanis, Ella; Auerbach, Leo; Azzollini, Jacopo; Balmaña, Judith; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Benitez, Javier; Berger, Andreas; Berger, Raanan; Blanco, Amie M.; Blazer, Kathleen R.; Blok, Marinus J.; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R.; Brewer, Carole; Buecher, Bruno; Buys, Saundra S.; Caldes, Trinidad; Caliebe, Almuth; Caligo, Maria A.; Campbell, Ian; Caputo, Sandrine M.; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B.M.; Collée, J. Margriet; Cook, Jackie; Davidson, Rosemarie; de la Hoya, Miguel; De Leeneer, Kim; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Domchek, Susan M.; Dorfling, Cecilia M.; Velazquez, Carolina; Dworniczak, Bernd; Eason, Jacqueline; Easton, Douglas F.; Eeles, Ros; Ehrencrona, Hans; Ejlertsen, Bent; emBRAce; Engel, Christoph; Engert, Stefanie; Evans, D. Gareth; Faivre, Laurence; Feliubadaló, Lidia; Ferrer, Sandra Fert; Foretova, Lenka; Fowler, Jeffrey; Frost, Debra; Galvão, Henrique C.R.; Ganz, Patricia A.; Garber, Judy; Gauthier-Villars, Marion; Gehrig, Andrea; GEMO Study Collaborators; Gerdes, Anne Marie; Gesta, Paul; Giannini, Giuseppe; Giraud, Sophie; Glendon, Gord; Godwin, Andrew K.; Greene, Mark H.; Gronwald, Jacek; Gutierrez-Barrera, Angelica; Hahnen, Eric; Hauke, Jan; HeBon; Henderson, Alex; Hentschel, Julia; Hogervorst, Frans B.L.; Honisch, Ellen; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Vijai, Joseph; Kaczmarek, Katarzyna; Karlan, Beth Y.; Kast, Karin; Kim, Sung Won; Konstantopoulou, Irene; Korach, Jacob; Laitman, Yael; Lasa, Adriana; Lasset, Christine; Lázaro, Conxi; Lee, Annette; Lee, Min Hyuk; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lindor, Noralane M.; Longy, Michel; Loud, Jennifer T.; Lu, Karen H.; Lubinski, Jan; Machackova, Eva; Manoukian, Siranoush; Mari, Véronique; Martínez-Bouzas, Cristina; Matrai, Zoltan; Mebirouk, Noura; Meijers-Heijboer, Hanne E.J.; Meindl, Alfons; Mensenkamp, Arjen R.; Mickys, Ugnius; Miller, Austin; Montagna, Marco; Moysich, Kirsten B.; Mulligan, Anna Marie; Musinsky, Jacob; Neuhausen, Susan L.; Nevanlinna, Heli; Ngeow, Joanne; Nguyen, Huu Phuc; Niederacher, Dieter; Nielsen, Henriette Roed; Nielsen, Finn Cilius; Nussbaum, Robert L.; Offit, Kenneth; Öfverholm, Anna; Ong, Kai Ren; Osorio, Ana; Papi, Laura; Papp, Janos; Pasini, Barbara; Pedersen, Inge Sokilde; Peixoto, Ana; Peruga, Nina; Peterlongo, Paolo; Pohl, Esther; Pradhan, Nisha; Prajzendanc, Karolina; Prieur, Fabienne; Pujol, Pascal; Radice, Paolo; Ramus, Susan J.; Rantala, Johanna; Rashid, Muhammad Usman; Rhiem, Kerstin; Robson, Mark; Rodriguez, Gustavo C.; Rogers, Mark T.; Rudaitis, Vilius; Schmidt, Ane Y.; Schmutzler, Rita Katharina; Senter, Leigha; Shah, Payal D.; Sharma, Priyanka; Side, Lucy E.; Simard, Jacques; Singer, Christian F.; Skytte, Anne Bine; Slavin, Thomas P.; Snape, Katie; Sobol, Hagay; Southey, Melissa; Steele, Linda; Steinemann, Doris; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tan, Yen Y.; Teixeira, Manuel R.; Terry, Mary Beth; Teulé, Alex; Thomas, Abigail; Thull, Darcy L.; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Topka, Sabine; Trainer, Alison H.; Tung, Nadine; van Asperen, Christi J.; van der Hout, Annemieke H.; van der Kolk, Lizet E.; van der Luijt, Rob B.; Van Heetvelde, Mattias; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Villarreal-Garza, Cynthia; von Wachenfeldt, Anna; Walker, Lisa; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weber, Bernhard H.F.; Yannoukakos, Drakoulis; Yoon, Sook Yee; Zanzottera, Cristina; Zidan, Jamal; Zorn, Kristin K.; Hutten Selkirk, Christina G.; Hulick, Peter J.; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Antoniou, Antonis C.; Nathanson, Katherine L.; kConFab Investigators.
In: Human Mutation, Vol. 39, No. 5, 01.05.2018, p. 593-620.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations
AU - Rebbeck, Timothy R.
AU - Friebel, Tara M.
AU - Friedman, Eitan
AU - Hamann, Ute
AU - Huo, Dezheng
AU - Kwong, Ava
AU - Olah, Edith
AU - Olopade, Olufunmilayo I.
AU - Solano, Angela R.
AU - Teo, Soo Hwang
AU - Thomassen, Mads
AU - Weitzel, Jeffrey N.
AU - Chan, T. L.
AU - Couch, Fergus J.
AU - Goldgar, David E.
AU - Kruse, Torben A.
AU - Palmero, Edenir Inêz
AU - Park, Sue Kyung
AU - Torres, Diana
AU - McGuffog, Lesley
AU - van Rensburg, Elizabeth J.
AU - Parsons, Michael T.
AU - Leslie, Goska
AU - Aalfs, Cora M.
AU - Abugattas, Julio
AU - Adlard, Julian
AU - Agata, Simona
AU - Aittomäki, Kristiina
AU - Andrews, Lesley
AU - Andrulis, Irene L.
AU - Arason, Adalgeir
AU - Arnold, Norbert
AU - Arun, Banu K.
AU - Asseryanis, Ella
AU - Auerbach, Leo
AU - Azzollini, Jacopo
AU - Balmaña, Judith
AU - Barile, Monica
AU - Barkardottir, Rosa B.
AU - Barrowdale, Daniel
AU - Benitez, Javier
AU - Berger, Andreas
AU - Berger, Raanan
AU - Blanco, Amie M.
AU - Blazer, Kathleen R.
AU - Blok, Marinus J.
AU - Bonadona, Valérie
AU - Bonanni, Bernardo
AU - Bradbury, Angela R.
AU - Brewer, Carole
AU - Buecher, Bruno
AU - Buys, Saundra S.
AU - Caldes, Trinidad
AU - Caliebe, Almuth
AU - Caligo, Maria A.
AU - Campbell, Ian
AU - Caputo, Sandrine M.
AU - Chiquette, Jocelyne
AU - Chung, Wendy K.
AU - Claes, Kathleen B.M.
AU - Collée, J. Margriet
AU - Cook, Jackie
AU - Davidson, Rosemarie
AU - de la Hoya, Miguel
AU - De Leeneer, Kim
AU - de Pauw, Antoine
AU - Delnatte, Capucine
AU - Diez, Orland
AU - Ding, Yuan Chun
AU - Ditsch, Nina
AU - Domchek, Susan M.
AU - Dorfling, Cecilia M.
AU - Velazquez, Carolina
AU - Dworniczak, Bernd
AU - Eason, Jacqueline
AU - Easton, Douglas F.
AU - Eeles, Ros
AU - Ehrencrona, Hans
AU - Ejlertsen, Bent
AU - emBRAce
AU - Engel, Christoph
AU - Engert, Stefanie
AU - Evans, D. Gareth
AU - Faivre, Laurence
AU - Feliubadaló, Lidia
AU - Ferrer, Sandra Fert
AU - Foretova, Lenka
AU - Fowler, Jeffrey
AU - Frost, Debra
AU - Galvão, Henrique C.R.
AU - Ganz, Patricia A.
AU - Garber, Judy
AU - Gauthier-Villars, Marion
AU - Gehrig, Andrea
AU - GEMO Study Collaborators
AU - Gerdes, Anne Marie
AU - Gesta, Paul
AU - Giannini, Giuseppe
AU - Giraud, Sophie
AU - Glendon, Gord
AU - Godwin, Andrew K.
AU - Greene, Mark H.
AU - Gronwald, Jacek
AU - Gutierrez-Barrera, Angelica
AU - Hahnen, Eric
AU - Hauke, Jan
AU - HeBon
AU - Henderson, Alex
AU - Hentschel, Julia
AU - Hogervorst, Frans B.L.
AU - Honisch, Ellen
AU - Imyanitov, Evgeny N.
AU - Isaacs, Claudine
AU - Izatt, Louise
AU - Izquierdo, Angel
AU - Jakubowska, Anna
AU - James, Paul
AU - Janavicius, Ramunas
AU - Jensen, Uffe Birk
AU - John, Esther M.
AU - Vijai, Joseph
AU - Kaczmarek, Katarzyna
AU - Karlan, Beth Y.
AU - Kast, Karin
AU - Kim, Sung Won
AU - Konstantopoulou, Irene
AU - Korach, Jacob
AU - Laitman, Yael
AU - Lasa, Adriana
AU - Lasset, Christine
AU - Lázaro, Conxi
AU - Lee, Annette
AU - Lee, Min Hyuk
AU - Lester, Jenny
AU - Lesueur, Fabienne
AU - Liljegren, Annelie
AU - Lindor, Noralane M.
AU - Longy, Michel
AU - Loud, Jennifer T.
AU - Lu, Karen H.
AU - Lubinski, Jan
AU - Machackova, Eva
AU - Manoukian, Siranoush
AU - Mari, Véronique
AU - Martínez-Bouzas, Cristina
AU - Matrai, Zoltan
AU - Mebirouk, Noura
AU - Meijers-Heijboer, Hanne E.J.
AU - Meindl, Alfons
AU - Mensenkamp, Arjen R.
AU - Mickys, Ugnius
AU - Miller, Austin
AU - Montagna, Marco
AU - Moysich, Kirsten B.
AU - Mulligan, Anna Marie
AU - Musinsky, Jacob
AU - Neuhausen, Susan L.
AU - Nevanlinna, Heli
AU - Ngeow, Joanne
AU - Nguyen, Huu Phuc
AU - Niederacher, Dieter
AU - Nielsen, Henriette Roed
AU - Nielsen, Finn Cilius
AU - Nussbaum, Robert L.
AU - Offit, Kenneth
AU - Öfverholm, Anna
AU - Ong, Kai Ren
AU - Osorio, Ana
AU - Papi, Laura
AU - Papp, Janos
AU - Pasini, Barbara
AU - Pedersen, Inge Sokilde
AU - Peixoto, Ana
AU - Peruga, Nina
AU - Peterlongo, Paolo
AU - Pohl, Esther
AU - Pradhan, Nisha
AU - Prajzendanc, Karolina
AU - Prieur, Fabienne
AU - Pujol, Pascal
AU - Radice, Paolo
AU - Ramus, Susan J.
AU - Rantala, Johanna
AU - Rashid, Muhammad Usman
AU - Rhiem, Kerstin
AU - Robson, Mark
AU - Rodriguez, Gustavo C.
AU - Rogers, Mark T.
AU - Rudaitis, Vilius
AU - Schmidt, Ane Y.
AU - Schmutzler, Rita Katharina
AU - Senter, Leigha
AU - Shah, Payal D.
AU - Sharma, Priyanka
AU - Side, Lucy E.
AU - Simard, Jacques
AU - Singer, Christian F.
AU - Skytte, Anne Bine
AU - Slavin, Thomas P.
AU - Snape, Katie
AU - Sobol, Hagay
AU - Southey, Melissa
AU - Steele, Linda
AU - Steinemann, Doris
AU - Sukiennicki, Grzegorz
AU - Sutter, Christian
AU - Szabo, Csilla I.
AU - Tan, Yen Y.
AU - Teixeira, Manuel R.
AU - Terry, Mary Beth
AU - Teulé, Alex
AU - Thomas, Abigail
AU - Thull, Darcy L.
AU - Tischkowitz, Marc
AU - Tognazzo, Silvia
AU - Toland, Amanda Ewart
AU - Topka, Sabine
AU - Trainer, Alison H.
AU - Tung, Nadine
AU - van Asperen, Christi J.
AU - van der Hout, Annemieke H.
AU - van der Kolk, Lizet E.
AU - van der Luijt, Rob B.
AU - Van Heetvelde, Mattias
AU - Varesco, Liliana
AU - Varon-Mateeva, Raymonda
AU - Vega, Ana
AU - Villarreal-Garza, Cynthia
AU - von Wachenfeldt, Anna
AU - Walker, Lisa
AU - Wang-Gohrke, Shan
AU - Wappenschmidt, Barbara
AU - Weber, Bernhard H.F.
AU - Yannoukakos, Drakoulis
AU - Yoon, Sook Yee
AU - Zanzottera, Cristina
AU - Zidan, Jamal
AU - Zorn, Kristin K.
AU - Hutten Selkirk, Christina G.
AU - Hulick, Peter J.
AU - Chenevix-Trench, Georgia
AU - Spurdle, Amanda B.
AU - Antoniou, Antonis C.
AU - Nathanson, Katherine L.
AU - kConFab Investigators
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
KW - BRCA1
KW - BRCA2
KW - breast cancer
KW - ethnicity
KW - geography
KW - mutation
KW - ovarian cancer
UR - http://www.scopus.com/inward/record.url?scp=85043494756&partnerID=8YFLogxK
U2 - 10.1002/humu.23406
DO - 10.1002/humu.23406
M3 - Article
AN - SCOPUS:85043494756
VL - 39
SP - 593
EP - 620
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 5
ER -