Citations 2
ENIGMA CHEK2 gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk
Stolařová, Lenka , Kleiblová, Petra , Šťastná, Barbora , Janatová, Markéta , Soukupová, Jana , Achatz, Maria Isabel , Ambrosone, Christine B. , Apostolou, Paraskevi , Arun, Banu , Auer, Paul L. , Bertelsen, Birgitte , Japan, Biobank, Kamatani, Yoichiro, Morisaki, Takayuki , Nagai, Akiko , Muto, Kaori , Murakami, Yoshinori , Furukawa, Yoichi , Yamanashi, Yuji , Nakamura, Yusuke , Momozawa, Yukihide , Ohnishi, Yozo, Kubo, Michiaki , Higashiue, Shinichi , Kobayashi, Shuzo , Minami, Shiro, Yamaguhci, Hiroki, Arai, Hajime , Yamaji, Ken , Asai, Satoshi , Fujioka, Tomoaki, Obara, Wataru , Mori, Seijiro, Murayama, Shigeo , Miki, Yoshio , Masumoto, Akihide, Yamada, Akira , Nishizawa, Yasuko, Higashiyama, Masahiko, Kutsumi, Hiromu, Koretsune, Yukihiro , Blok, Marinus J. , Brunet, Joan , Calvello, Mariarosaria , Chen, Fei , Cortesi, Laura , Crujeiras-González, Ana , Černá, Marta , Hovhannisyan, Milena, Jelínková, Sandra , Nehasil, Petr , Macháčková, Eva , Krutilkova, Vera, Tavandzis, Spiros , Cerna, Leona, Chvojka, Štěpán, Koudová, Monika , Puchmajerová, Alena, Novotný, Jan , Veselá, Kamila , Hrušková, Lucie , Michalovska, Renata, Schwetzova, Denisa, Vlčková, Zdeňka, Černá, Monika, Hejnalová, Markéta, Jedlickova, Nikol, Šubrt, Ivan , Zavoral, Tomas, Kosařová, Marcela, Vacínová, Gabriela, Janíková, Mária , Kratochvílová, Romana , Curtisová, Václava , Vrtěl, Radek , Scheinost, Ondřej, Duskova, Petra, Putter, Robin De , Efremidis, Anna , Engel, Christoph , Evans, D. Gareth , Feliubadaló, Lídia , Fuentes-Ríos, Olivia , Gómez, E. , Haiman, Christopher A. , Hansen, Thomas van Overeem , Hodge, James M. , Huang, Hongyan , Ishak, Nur Diana Binte , Iwasaki, Yusuke , Konstantopoulou, Irene , Li, Na , Lindström, Sara , Lori, Adriana , Martinez, Elana, Martins, Alexandra , McInerny, Simone , Montagna, Marco , Mori, Luigi , Nathanson, Katherine L. , Patel, Alpa V. , Poppe, Bruce , Rosseel, Toon , Ruddy, Kathryn J. , Santos, Elizabeth Santana Dos , Vachon, Celine M. , Volk, Alexander E. , Weber‐Lassalle, Nana , Weitzel, Jeffrey N. , Yadav, Siddhartha , Zethoven, Magnus, Zhang, Ze Wen, Vega, Ana , Rossing, Maria , Valle, Jesús Del , Nicolo, Arcangela De , Hahnen, Eric , Ngeow, Joanne , Kleibl, Zdeněk , Chen, Chen , Zemankova, Petra , Stastna, Barbora , Janatova, Marketa , Soukupova, Jana , Achatz, M I , Ambrosone, Christine B , Apostolou, Paraskevi , Arun, Banu , Auer, Paul , Barnard, Mollie , Bertelsen, Birgitte , Blok, Marinus J , Boddicker, Nicholas J , Brunet, Joan , Burnside, Elizabeth S , Calvello, Mariarosaria , Campbell, Ian G , Chan, Sock Hoai , Chen, Fei , Chiang, Jian Bang , Coppa, Anna , Cortesi, Laura , Crujeiras-González, Ana , De Leeneer, Kim , de Putter, Robin , DePersia, Allison , Devereux, Lisa , Domchek, Susan M , Efremidis, Anna , Engel, Christoph , Ernst, Corinna , Evans, D Gareth , Feliubadaló, Lidia , Fostira, Florentia , Fuentes-Ríos, Olivia , Gómez-García, Encarna B , González, Sara , Haiman, Christopher A , Hansen, Thomas van Overeem , Hauke, Jan , Hodge, James M , Hu, Chunling , Huang, Hongyan , Ishak, Nur Diana Binte , Iwasaki, Yusuke , Konstantopoulou, Irene , Kraft, Peter , Lacey, James V. , Lazaro, Conxi , Li, Na , Lim, Weng Khong , Lindstrom, Sara , Lori, Adriana , Martı́nez, Marı́a Elena , Martins, Alexandra , Matsuda, Koichi , Matullo, Giuseppe , McInerny, Simone , Michailidou, Kyriaki , Montagna, Marco , Monteiro, Alvaro N , Mori, Luigi , Nathanson, Katherine L , Neuhausen, Susan L. , Nevanlinna, H , Olson, Janet E , Palmer, Julie R , Pasini, Barbara , Patel, Alpa V , Piane, Maria , Poppe, Bruce , Radice, Paolo , Renieri, Alessandra , Resta, Nicoletta , Richardson, Marcy E , Rosseel, Toon , Ruddy, Kathryn J , Santamariña, Marta , Dos Santos, Elizabeth Santana , Teras, Lauren R , Toland, Amanda Ewart , Trentham-Dietz, Amy , Vachon, Celine M. , Volk, Alexander E , Weber-Lassalle, Nana , Weitzel, Jeffrey N , Wiesmuller, Lisa , Winham, Stacey J , Yadav, Siddhartha , Yannoukakos, Drakoulis , Yao, Song , Zampiga, Valentina , Zethoven, Magnus , Zhang, Ze Wen , Zima, Tomas , Spurdle, Amanda B , Vega, Ana , Rossing, Maria , Del Valle, Jesús , De Nicolo, Arcangela , Hahnen, Eric , Claes, Kathleen B M , Ngeow, Joanne , Momozawa, Yukihide , James, Paul , Couch, Fergus J. , Macurek, Libor , Kleibl, Zdenek , Chen, C , Japan, Biobank, Kamatani, Yoichiro, Mushiroda, Taisei , Tanaka, Toshihiro , Yamaguhci, Hiroki, Okazaki, Yasushi , Takahashi, Yasuo , Nagayama, Satoshi , Yoshiyama, Takashi , Boddicker, Nicholas , Burnside, Elizabeth S. , Campbell, Ian , Borecká, Marianna , Foretová, Lenka , Havránek, Ondřej , Vočka, Michal , Michalovska, Renata, Schwetzova, Denisa, Jedlickova, Nikol, Zavoral, Tomáš, Duskova, Petra, Stránecký, Viktor , Leeneer, Kim De , Domchek, Susan M. , González, Sara , Hauke, Jan , Hu, Chunling , Kraft, Peter , Lázaro, Conxi , Matullo, Giuseppe , Michailidou, Kyriaki , Monteiro, Álvaro N.A. , Nevanlinna, Heli , Olson, Janet E. , Palmer, Julie R. , Pasini, Barbara , Radice, Paolo , Renieri, Alessandra , Santamariña, Marta , Teras, Lauren R. , Trentham‐Dietz, Amy , Wiesmüller, Lisa , Winham, Stacey J. , Yannoukakos, Drakoulis , Yao, Song , Zampiga, Valentina , Spurdle, Amanda B. , Claes, Kathleen , James, Paul A. , Couch, Fergus J.
Clinical Cancer Research | July 14, 2023 | Volume: 29 | Issue: 16 | Pages: 3037-3050
Abstract Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.
No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing
Easton, Douglas F. , Lesueur, Fabienne , Decker, Brennan , Michailidou, Kyriaki , Li, Jun , Allen, Jamie , Luccarini, Craig , Pooley, Karen A. , Shah, Mitul , Bolla, Manjeet K. , Wang, Qin, Ahmad, Jamil , Thompson, Ella R. , Pertesi, Maroulio , Voegele, Catherine , Mebirouk, Noura, Robinot, Nivonirina , Forey, Nathalie, Luben, Robert , Aittomäki, Kristiina, Group, Australian Ovarian Cancer Study, Baynes, Caroline, Beckman, Matthias W., Benı́tez, Javier , Blot, William J. , Bogdanova, Natalia , Bojesen, Stig E. , Brenner, Hermann , Chang‐Claude, Jenny , Chia, Kee Seng , Choi, Ji‐Yeob , Conroy, Don, Darabi, Hatef, Devilee, Peter , Eriksson, Mikael , Fasching, Peter A. , Figueroa, Jonine D. , Flyger, Henrik, García‐Closas, Montserrat , Giles, Graham G. , Glendon, Gord, Guénel, Pascal , Haiman, Christopher A., Hart, Steven N. , Hartman, Mikael , Hooning, Maartje J. , Hsiung, Chia‐Ni , Jakubowska, Anna , James, Paul A. , John, Esther M. , Johnson, Nichola , Jones, Michael E. , Kabisch, Maria, Kang, Daehee , Investigators, kConFab, Kosma, Veli‐Matti , Kristensen, Vessela, Lambrechts, Diether , Li, Na , Investigators, Lifepool, Lindblom, Annika , Long, Jirong , Lophatananon, Artitaya, Lubiński, Jan , Mannermaa, Arto, Manoukian, Siranoush , Margolin, Sara , Matsuo, Keitaro , Meindl, Alfons , Mitchell, Gillian, Investigators, NBCS, Nevelsteen, Ines, Ouweland, Ans van den, Peterlongo, Paolo , Phuah, Sze Yee, Pylkäs, Katri , Rowley, Simone M. , Sangrajrang, Suleeporn , Schmutzler, Rita K., Shen, Chen‐Yang , Southey, Melissa C. , Surowy, Harald , Swerdlow, Anthony J. , Teo, Soo‐Hwang , Tollenaar, Rob A.�E.�M. , Tomlinson, Ian , Torres, Diana , Truong, Thérèse , Vachon, Celine M. , Verhoef, Senno, Wong‐Brown, Michelle W. , Zheng, Wei , Zheng, Ying , Scott, Rodney J. , Andrulis, Irene L. , Wu, Anna H. , Hopper, John L. , Winqvist, Robert , Burwinkel, Barbara , Sawyer, Elinor J. , Schmidt, Marjanka K. , Dörk, Thilo , Brauch, Hiltrud , Hamann, Ute, Fletcher, Olivia , Campbell, Ian , Dunning, Alison M. , Calvez‐Kelm, Florence Le , Goldgar, David E, Tavtigian, Sean V. , Chenevix‐Trench, Georgia , Thorne, Heather , Lambrechts, Diether , Luben, Robert N , Vachon, Celine, Decker, Brennan , Wang, Qin, Dennis, Joe , Damiola, Francesca , Durand, Geoffroy , Ahmed, Shahana , Anton‐Culver, Hoda , Arndt, Volker , Group, Australian Ovarian Cancer Study, Berg, David Van Den , Cox, Angela , Cross, Simon S. , Czene, Kamila , Eriksson, Mikael , Fostira, Florentia , González‐Neira, Anna , Hall, Per N , Hooning, Maartje J. , Ito, Hidemi , Investigators, kConFab, Kristensen, Vessela N. , Investigators, Lifepool, Mannermaa, Arto, Meindl, Alfons , Muir, Kenneth , Investigators, NBCS, Shu, Xiao‐Ou , Vachon, Celine M. , Nevanlinna, Heli , Couch, Fergus J. , Rudolph, Anja , Neuhausen, Susan L. , Milne, Roger L. , Pharoah, Paul D.P. , Goldgar, David E, Dörk, Thilo , Lambrechts, Diether , Giles, Graham G , James, Paul , Lesueur, Fabienne , Peterlongo, Paolo , Teo, Soo H , Swerdlow, Anthony J , Campbell, Ian G , John, Esther M , Southey, Melissa C , Matsuo, Keitaro , Hart, Steven N , Dunning, Alison M , Jakubowska, Anna , Jones, Michael E , Lambrechts, Diether , Brenner, Hermann , Guénel, Pascal , Hartman, Mikael , Torres, Diana , García-Closas, Montserrat , Schmidt, Marjanka K , Michailidou, Kyriaki , Bogdanova, Natalia V , Benitez, Javier , Chenevix-Trench, Georgia , Zheng, Wei , Figueroa, Jonine D , Pylkäs, Katri , Devilee, Peter , Manoukian, Siranoush , Lubinski, Jan , Fletcher, Olivia , Bojesen, Stig E , Truong, Therese , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J , Kang, Daehee
Journal of Medical Genetics | April 22, 2016 | Volume: 53 | Issue: 5 | Pages: 298-309
Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.