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

Timothy R. Rebbeck, Tara M. Friebel, Eitan Friedman, Ute Hamann, Dezheng Huo, Ava Kwong, Edith Olah, Olufunmilayo I. Olopade, Angela R. Solano, Soo Hwang Teo, Mads Thomassen, Jeffrey N. Weitzel, T. L. Chan, Fergus J. Couch, David E. Goldgar, Torben A. Kruse, Edenir Inêz Palmero, Sue Kyung Park, Diana Torres, Lesley McGuffog & 225 others Elizabeth J. van Rensburg, Michael T. Parsons, Goska Leslie, Cora M. Aalfs, Julio Abugattas, Julian Adlard, Simona Agata, Kristiina Aittomäki, Lesley Andrews, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Ella Asseryanis, Leo Auerbach, Jacopo Azzollini, Judith Balmaña, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Andreas Berger, Raanan Berger, Amie M. Blanco, Kathleen R. Blazer, Marinus J. Blok, Valérie Bonadona, Bernardo Bonanni, Angela R. Bradbury, Carole Brewer, Bruno Buecher, Saundra S. Buys, Trinidad Caldes, Almuth Caliebe, Maria A. Caligo, Ian Campbell, Sandrine M. Caputo, Jocelyne Chiquette, Wendy K. Chung, Kathleen B.M. Claes, J. Margriet Collée, Jackie Cook, Rosemarie Davidson, Miguel de la Hoya, Kim De Leeneer, Antoine de Pauw, Capucine Delnatte, Orland Diez, Yuan Chun Ding, Nina Ditsch, Susan M. Domchek, Cecilia M. Dorfling, Carolina Velazquez, Bernd Dworniczak, Jacqueline Eason, Douglas F. Easton, Ros Eeles, Hans Ehrencrona, Bent Ejlertsen, emBRAce, Christoph Engel, Stefanie Engert, D. Gareth Evans, Laurence Faivre, Lidia Feliubadaló, Sandra Fert Ferrer, Lenka Foretova, Jeffrey Fowler, Debra Frost, Henrique C.R. Galvão, Patricia A. Ganz, Judy Garber, Marion Gauthier-Villars, Andrea Gehrig, GEMO Study Collaborators, Anne Marie Gerdes, Paul Gesta, Giuseppe Giannini, Sophie Giraud, Gord Glendon, Andrew K. Godwin, Mark H. Greene, Jacek Gronwald, Angelica Gutierrez-Barrera, Eric Hahnen, Jan Hauke, HeBon, Alex Henderson, Julia Hentschel, Frans B.L. Hogervorst, Ellen Honisch, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Joseph Vijai, Katarzyna Kaczmarek, Beth Y. Karlan, Karin Kast, KCon Fab Investigators, Sung Won Kim, Irene Konstantopoulou, Jacob Korach, Yael Laitman, Adriana Lasa, Christine Lasset, Conxi Lázaro, Annette Lee, Min Hyuk Lee, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Noralane M. Lindor, Michel Longy, Jennifer T. Loud, Karen H. Lu, Jan Lubinski, Eva Machackova, Siranoush Manoukian, Véronique Mari, Cristina Martínez-Bouzas, Zoltan Matrai, Noura Mebirouk, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Ugnius Mickys, Austin Miller, Marco Montagna, Kirsten B. Moysich, Anna Marie Mulligan, Jacob Musinsky, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow, Huu Phuc Nguyen, Dieter Niederacher, Henriette Roed Nielsen, Finn Cilius Nielsen, Robert L. Nussbaum, Kenneth Offit, Anna Öfverholm, Kai Ren Ong, Ana Osorio, Laura Papi, Janos Papp, Barbara Pasini, Inge Sokilde Pedersen, Ana Peixoto, Nina Peruga, Paolo Peterlongo, Esther Pohl, Nisha Pradhan, Karolina Prajzendanc, Fabienne Prieur, Pascal Pujol, Paolo Radice, Susan J. Ramus, Johanna Rantala, Muhammad Usman Rashid, Kerstin Rhiem, Mark Robson, Gustavo C. Rodriguez, Mark T. Rogers, Vilius Rudaitis, Ane Y. Schmidt, Rita Katharina Schmutzler, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Jacques Simard, Christian F. Singer, Anne Bine Skytte, Thomas P. Slavin, Katie Snape, Hagay Sobol, Melissa Southey, Linda Steele, Doris Steinemann, Grzegorz Sukiennicki, Christian Sutter, Csilla I. Szabo, Yen Y. Tan, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Abigail Thomas, Darcy L. Thull, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Sabine Topka, Alison H. Trainer, Nadine Tung, Christi J. van Asperen, Annemieke H. van der Hout, Lizet E. van der Kolk, Rob B. van der Luijt, Mattias Van Heetvelde, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Cynthia Villarreal-Garza, Anna von Wachenfeldt, Lisa Walker, Shan Wang-Gohrke, Barbara Wappenschmidt, Bernhard H.F. Weber, Drakoulis Yannoukakos, Sook Yee Yoon, Cristina Zanzottera, Jamal Zidan, Kristin K. Zorn, Christina G. Hutten Selkirk, Peter J. Hulick, Georgia Chenevix-Trench, Amanda B. Spurdle, Antonis C. Antoniou, Katherine L. Nathanson

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)593-620
Number of pages28
JournalHuman Mutation
Volume39
Issue number5
DOIs
Publication statusPublished - 1 May 2018
Externally publishedYes

Keywords

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

Cite this

Rebbeck, T. R., Friebel, T. M., Friedman, E., Hamann, U., Huo, D., Kwong, A., ... Nathanson, K. L. (2018). Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Human Mutation, 39(5), 593-620. https://doi.org/10.1002/humu.23406
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 ; Investigators, KCon Fab ; 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. / Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. In: Human Mutation. 2018 ; Vol. 39, No. 5. pp. 593-620.
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title = "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.",
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author = "Rebbeck, {Timothy R.} and Friebel, {Tara M.} and Eitan Friedman and Ute Hamann and Dezheng Huo and Ava Kwong and Edith Olah and Olopade, {Olufunmilayo I.} and Solano, {Angela R.} and Teo, {Soo Hwang} and Mads Thomassen and Weitzel, {Jeffrey N.} and Chan, {T. L.} and Couch, {Fergus J.} and Goldgar, {David E.} and Kruse, {Torben A.} and Palmero, {Edenir In{\^e}z} and Park, {Sue Kyung} and Diana Torres and Lesley McGuffog and {van Rensburg}, {Elizabeth J.} and Parsons, {Michael T.} and Goska Leslie and Aalfs, {Cora M.} and Julio Abugattas and Julian Adlard and Simona Agata and Kristiina Aittom{\"a}ki and Lesley Andrews and Andrulis, {Irene L.} and Adalgeir Arason and Norbert Arnold and Arun, {Banu K.} and Ella Asseryanis and Leo Auerbach and Jacopo Azzollini and Judith Balma{\~n}a and Monica Barile and Barkardottir, {Rosa B.} and Daniel Barrowdale and Javier Benitez and Andreas Berger and Raanan Berger and Blanco, {Amie M.} and Blazer, {Kathleen R.} and Blok, {Marinus J.} and Val{\'e}rie Bonadona and Bernardo Bonanni and Bradbury, {Angela R.} and Carole Brewer and Bruno Buecher and Buys, {Saundra S.} and Trinidad Caldes and Almuth Caliebe and Caligo, {Maria A.} and Ian Campbell and Caputo, {Sandrine M.} and Jocelyne Chiquette and Chung, {Wendy K.} and Claes, {Kathleen B.M.} and Coll{\'e}e, {J. Margriet} and Jackie Cook and Rosemarie Davidson and {de la Hoya}, Miguel and {De Leeneer}, Kim and {de Pauw}, Antoine and Capucine Delnatte and Orland Diez and Ding, {Yuan Chun} and Nina Ditsch and Domchek, {Susan M.} and Dorfling, {Cecilia M.} and Carolina Velazquez and Bernd Dworniczak and Jacqueline Eason and Easton, {Douglas F.} and Ros Eeles and Hans Ehrencrona and Bent Ejlertsen and emBRAce and Christoph Engel and Stefanie Engert and Evans, {D. Gareth} and Laurence Faivre and Lidia Feliubadal{\'o} and Ferrer, {Sandra Fert} and Lenka Foretova and Jeffrey Fowler and Debra Frost and Galv{\~a}o, {Henrique C.R.} and Ganz, {Patricia A.} and Judy Garber and Marion Gauthier-Villars and Andrea Gehrig and {GEMO Study Collaborators} and Gerdes, {Anne Marie} and Paul Gesta and Giuseppe Giannini and Sophie Giraud and Gord Glendon and Godwin, {Andrew K.} and Greene, {Mark H.} and Jacek Gronwald and Angelica Gutierrez-Barrera and Eric Hahnen and Jan Hauke and HeBon and Alex Henderson and Julia Hentschel and Hogervorst, {Frans B.L.} and Ellen Honisch and Imyanitov, {Evgeny N.} and Claudine Isaacs and Louise Izatt and Angel Izquierdo and Anna Jakubowska and Paul James and Ramunas Janavicius and Jensen, {Uffe Birk} and John, {Esther M.} and Joseph Vijai and Katarzyna Kaczmarek and Karlan, {Beth Y.} and Karin Kast and Investigators, {KCon Fab} and Kim, {Sung Won} and Irene Konstantopoulou and Jacob Korach and Yael Laitman and Adriana Lasa and Christine Lasset and Conxi L{\'a}zaro and Annette Lee and Lee, {Min Hyuk} and Jenny Lester and Fabienne Lesueur and Annelie Liljegren and Lindor, {Noralane M.} and Michel Longy and Loud, {Jennifer T.} and Lu, {Karen H.} and Jan Lubinski and Eva Machackova and Siranoush Manoukian and V{\'e}ronique Mari and Cristina Mart{\'i}nez-Bouzas and Zoltan Matrai and Noura Mebirouk and Meijers-Heijboer, {Hanne E.J.} and Alfons Meindl and Mensenkamp, {Arjen R.} and Ugnius Mickys and Austin Miller and Marco Montagna and Moysich, {Kirsten B.} and Mulligan, {Anna Marie} and Jacob Musinsky and Neuhausen, {Susan L.} and Heli Nevanlinna and Joanne Ngeow and Nguyen, {Huu Phuc} and Dieter Niederacher and Nielsen, {Henriette Roed} and Nielsen, {Finn Cilius} and Nussbaum, {Robert L.} and Kenneth Offit and Anna {\"O}fverholm and Ong, {Kai Ren} and Ana Osorio and Laura Papi and Janos Papp and Barbara Pasini and Pedersen, {Inge Sokilde} and Ana Peixoto and Nina Peruga and Paolo Peterlongo and Esther Pohl and Nisha Pradhan and Karolina Prajzendanc and Fabienne Prieur and Pascal Pujol and Paolo Radice and Ramus, {Susan J.} and Johanna Rantala and Rashid, {Muhammad Usman} and Kerstin Rhiem and Mark Robson and Rodriguez, {Gustavo C.} and Rogers, {Mark T.} and Vilius Rudaitis and Schmidt, {Ane Y.} and Schmutzler, {Rita Katharina} and Leigha Senter and Shah, {Payal D.} and Priyanka Sharma and Side, {Lucy E.} and Jacques Simard and Singer, {Christian F.} and Skytte, {Anne Bine} and Slavin, {Thomas P.} and Katie Snape and Hagay Sobol and Melissa Southey and Linda Steele and Doris Steinemann and Grzegorz Sukiennicki and Christian Sutter and Szabo, {Csilla I.} and Tan, {Yen Y.} and Teixeira, {Manuel R.} and Terry, {Mary Beth} and Alex Teul{\'e} and Abigail Thomas and Thull, {Darcy L.} and Marc Tischkowitz and Silvia Tognazzo and Toland, {Amanda Ewart} and Sabine Topka and Trainer, {Alison H.} and Nadine Tung and {van Asperen}, {Christi J.} and {van der Hout}, {Annemieke H.} and {van der Kolk}, {Lizet E.} and {van der Luijt}, {Rob B.} and {Van Heetvelde}, Mattias and Liliana Varesco and Raymonda Varon-Mateeva and Ana Vega and Cynthia Villarreal-Garza and {von Wachenfeldt}, Anna and Lisa Walker and Shan Wang-Gohrke and Barbara Wappenschmidt and Weber, {Bernhard H.F.} and Drakoulis Yannoukakos and Yoon, {Sook Yee} and Cristina Zanzottera and Jamal Zidan and Zorn, {Kristin K.} and {Hutten Selkirk}, {Christina G.} and Hulick, {Peter J.} and Georgia Chenevix-Trench and Spurdle, {Amanda B.} and Antoniou, {Antonis C.} and Nathanson, {Katherine L.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1002/humu.23406",
language = "English",
volume = "39",
pages = "593--620",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Blackwell",
number = "5",

}

Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, SH, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, McGuffog, L, van Rensburg, EJ, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomäki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmaña, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collée, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, emBRAce, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadaló, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvão, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, GEMO Study Collaborators, Gerdes, AM, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, HeBon, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Investigators, KCF, Kim, SW, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lázaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martínez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Öfverholm, A, Ong, KR, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, AB, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teulé, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, SY, Zanzottera, C, Zidan, J, Zorn, KK, Hutten Selkirk, CG, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC & Nathanson, KL 2018, 'Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations' Human Mutation, vol. 39, no. 5, pp. 593-620. https://doi.org/10.1002/humu.23406

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; Investigators, KCon Fab; 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.

In: Human Mutation, Vol. 39, No. 5, 01.05.2018, p. 593-620.

Research output: Contribution to journalArticleResearchpeer-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 - Investigators, KCon Fab

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.

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

VL - 39

SP - 593

EP - 620

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 5

ER -

Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Human Mutation. 2018 May 1;39(5):593-620. https://doi.org/10.1002/humu.23406