ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk
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, hamperin...
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| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Online Access: | https://hdl.handle.net/10356/174196 |
| _version_ | 1824455658306535424 |
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| author | Stolarova, Lenka Kleiblova, Petra Zemankova, Petra Stastna, Barbora Janatova, Marketa Soukupova, Jana Achatz, Maria Isabel Ambrosone, Christine Apostolou, Paraskevi Arun, Banu K. Auer, Paul Barnard, Mollie Bertelsen, Birgitte Blok, Marinus J. Boddicker, Nicholas Brunet, Joan Burnside, Elizabeth S. Calvello, Mariarosaria Campbell, Ian 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 Efremidis, Anna Engel, Christoph Ernst, Corinna Evans, D. Gareth R. Feliubadaló, Lidia Fostira, Florentia Fuentes-Ríos, Olivia Gómez-García, Encarna B. González, Sara Haiman, Christopher Hansen, Thomas van Overeem Hauke, Jan Hodge, James Hu, Chunling Huang, Hongyan Ishak, Nur Diana Binte Iwasaki, Yusuke Konstantopoulou, Irene Kraft, Peter Lacey, James Lázaro, Conxi Li, Na Lim, Weng Khong Lindstrom, Sara Lori, Adriana Martinez, Elana Martins, Alexandra Matsuda, Koichi Matullo, Giuseppe McInerny, Simone Michailidou, Kyriaki Montagna, Marco Monteiro, Alvaro N. A. Mori, Luigi Nathanson, Katherine Neuhausen, Susan L. Nevanlinna, Heli Olson, Janet E. Palmer, Julie Pasini, Barbara Patel, Alpa 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 Toland, Amanda E. Trentham-Dietz, Amy Vachon, Celine M. Volk, Alexander E. Weber-Lassalle, Nana Weitzel, Jeffrey N. Wiesmuller, Lisa Winham, Stacey 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 A. Couch, Fergus J. Macurek, Libor Kleibl, Zdenek |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Stolarova, Lenka Kleiblova, Petra Zemankova, Petra Stastna, Barbora Janatova, Marketa Soukupova, Jana Achatz, Maria Isabel Ambrosone, Christine Apostolou, Paraskevi Arun, Banu K. Auer, Paul Barnard, Mollie Bertelsen, Birgitte Blok, Marinus J. Boddicker, Nicholas Brunet, Joan Burnside, Elizabeth S. Calvello, Mariarosaria Campbell, Ian 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 Efremidis, Anna Engel, Christoph Ernst, Corinna Evans, D. Gareth R. Feliubadaló, Lidia Fostira, Florentia Fuentes-Ríos, Olivia Gómez-García, Encarna B. González, Sara Haiman, Christopher Hansen, Thomas van Overeem Hauke, Jan Hodge, James Hu, Chunling Huang, Hongyan Ishak, Nur Diana Binte Iwasaki, Yusuke Konstantopoulou, Irene Kraft, Peter Lacey, James Lázaro, Conxi Li, Na Lim, Weng Khong Lindstrom, Sara Lori, Adriana Martinez, Elana Martins, Alexandra Matsuda, Koichi Matullo, Giuseppe McInerny, Simone Michailidou, Kyriaki Montagna, Marco Monteiro, Alvaro N. A. Mori, Luigi Nathanson, Katherine Neuhausen, Susan L. Nevanlinna, Heli Olson, Janet E. Palmer, Julie Pasini, Barbara Patel, Alpa 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 Toland, Amanda E. Trentham-Dietz, Amy Vachon, Celine M. Volk, Alexander E. Weber-Lassalle, Nana Weitzel, Jeffrey N. Wiesmuller, Lisa Winham, Stacey 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 A. Couch, Fergus J. Macurek, Libor Kleibl, Zdenek |
| author_sort | Stolarova, Lenka |
| collection | NTU |
| description | 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 ¼ 102), functionally intermediate (N ¼ 12), or functionally wild-type (WT)–like (N ¼ 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. |
| first_indexed | 2025-02-19T03:41:42Z |
| format | Journal Article |
| id | ntu-10356/174196 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:41:42Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1741962024-03-24T15:38:53Z ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk Stolarova, Lenka Kleiblova, Petra Zemankova, Petra Stastna, Barbora Janatova, Marketa Soukupova, Jana Achatz, Maria Isabel Ambrosone, Christine Apostolou, Paraskevi Arun, Banu K. Auer, Paul Barnard, Mollie Bertelsen, Birgitte Blok, Marinus J. Boddicker, Nicholas Brunet, Joan Burnside, Elizabeth S. Calvello, Mariarosaria Campbell, Ian 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 Efremidis, Anna Engel, Christoph Ernst, Corinna Evans, D. Gareth R. Feliubadaló, Lidia Fostira, Florentia Fuentes-Ríos, Olivia Gómez-García, Encarna B. González, Sara Haiman, Christopher Hansen, Thomas van Overeem Hauke, Jan Hodge, James Hu, Chunling Huang, Hongyan Ishak, Nur Diana Binte Iwasaki, Yusuke Konstantopoulou, Irene Kraft, Peter Lacey, James Lázaro, Conxi Li, Na Lim, Weng Khong Lindstrom, Sara Lori, Adriana Martinez, Elana Martins, Alexandra Matsuda, Koichi Matullo, Giuseppe McInerny, Simone Michailidou, Kyriaki Montagna, Marco Monteiro, Alvaro N. A. Mori, Luigi Nathanson, Katherine Neuhausen, Susan L. Nevanlinna, Heli Olson, Janet E. Palmer, Julie Pasini, Barbara Patel, Alpa 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 Toland, Amanda E. Trentham-Dietz, Amy Vachon, Celine M. Volk, Alexander E. Weber-Lassalle, Nana Weitzel, Jeffrey N. Wiesmuller, Lisa Winham, Stacey 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 A. Couch, Fergus J. Macurek, Libor Kleibl, Zdenek Lee Kong Chian School of Medicine (LKCMedicine) National Cancer Centre Medicine, Health and Life Sciences Breast carcinogenesis Germline mutation 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 ¼ 102), functionally intermediate (N ¼ 12), or functionally wild-type (WT)–like (N ¼ 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. Published version This work was supported by the grant projects of the Czech Ministry of Health NV19–03–00279, DRO-VFN-64165; Charles University projects COOPERATIO and SVV260516; Ministry of Education, Youths and Sports of the Czech Republic grant EXCELES no. LX22NPO05102 funded by EU. L. Stolarova was partially supported by Czech Academy of Science (PPPLZ project L200522201). The CARRIERS study was supported by NIH grants R01 CA192393, R35 CA253187 and a specialized program of research excellence (SPORE) in breast cancer (P50 CA116201). Contract grant sponsor A. Vega: supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (PI22/00589, PI19/01424; INT20/ 00071), the Autonomous Government of Galicia (Consolidation and structuring program: IN607B), by the Fundación Mutua Madrileña (call 2018), and by the AECC (PRYES211091VEGA). A.B. Spurdle was supported by an NHMRC Investigator Fellowship (APP177524). 2024-03-19T07:55:21Z 2024-03-19T07:55:21Z 2023 Journal Article Stolarova, L., Kleiblova, P., Zemankova, P., Stastna, B., Janatova, M., Soukupova, J., Achatz, M. I., Ambrosone, C., Apostolou, P., Arun, B. K., Auer, P., Barnard, M., Bertelsen, B., Blok, M. J., Boddicker, N., Brunet, J., Burnside, E. S., Calvello, M., Campbell, I., ...Kleibl, Z. (2023). ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk. Clinical Cancer Research, 29(16), 3037-3050. https://dx.doi.org/10.1158/1078-0432.CCR-23-0212 1078-0432 https://hdl.handle.net/10356/174196 10.1158/1078-0432.CCR-23-0212 37449874 2-s2.0-85168222787 16 29 3037 3050 en Clinical Cancer Research © 2023 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Breast carcinogenesis Germline mutation Stolarova, Lenka Kleiblova, Petra Zemankova, Petra Stastna, Barbora Janatova, Marketa Soukupova, Jana Achatz, Maria Isabel Ambrosone, Christine Apostolou, Paraskevi Arun, Banu K. Auer, Paul Barnard, Mollie Bertelsen, Birgitte Blok, Marinus J. Boddicker, Nicholas Brunet, Joan Burnside, Elizabeth S. Calvello, Mariarosaria Campbell, Ian 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 Efremidis, Anna Engel, Christoph Ernst, Corinna Evans, D. Gareth R. Feliubadaló, Lidia Fostira, Florentia Fuentes-Ríos, Olivia Gómez-García, Encarna B. González, Sara Haiman, Christopher Hansen, Thomas van Overeem Hauke, Jan Hodge, James Hu, Chunling Huang, Hongyan Ishak, Nur Diana Binte Iwasaki, Yusuke Konstantopoulou, Irene Kraft, Peter Lacey, James Lázaro, Conxi Li, Na Lim, Weng Khong Lindstrom, Sara Lori, Adriana Martinez, Elana Martins, Alexandra Matsuda, Koichi Matullo, Giuseppe McInerny, Simone Michailidou, Kyriaki Montagna, Marco Monteiro, Alvaro N. A. Mori, Luigi Nathanson, Katherine Neuhausen, Susan L. Nevanlinna, Heli Olson, Janet E. Palmer, Julie Pasini, Barbara Patel, Alpa 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 Toland, Amanda E. Trentham-Dietz, Amy Vachon, Celine M. Volk, Alexander E. Weber-Lassalle, Nana Weitzel, Jeffrey N. Wiesmuller, Lisa Winham, Stacey 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 A. Couch, Fergus J. Macurek, Libor Kleibl, Zdenek ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk |
| title | ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk |
| title_full | ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk |
| title_fullStr | ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk |
| title_full_unstemmed | ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk |
| title_short | ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk |
| title_sort | enigma chek2gether project a comprehensive study identifies functionally impaired chek2 germline missense variants associated with increased breast cancer risk |
| topic | Medicine, Health and Life Sciences Breast carcinogenesis Germline mutation |
| url | https://hdl.handle.net/10356/174196 |
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enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT olsonjanete enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT palmerjulie enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT pasinibarbara enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT patelalpa enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT pianemaria enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT poppebruce enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT radicepaolo enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT renierialessandra enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT restanicoletta enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT richardsonmarcye enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT rosseeltoon enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT ruddykathrynj 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enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT volkalexandere enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT weberlassallenana enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT weitzeljeffreyn enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT wiesmullerlisa enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT winhamstacey enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT yadavsiddhartha enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT yannoukakosdrakoulis enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT yaosong enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT zampigavalentina enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT zethovenmagnus enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT zhangzewen enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT zimatomas enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT spurdleamandab enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT vegaana enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT rossingmaria enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT delvallejesus enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT denicoloarcangela enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT hahneneric 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enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk AT kleiblzdenek enigmachek2getherprojectacomprehensivestudyidentifiesfunctionallyimpairedchek2germlinemissensevariantsassociatedwithincreasedbreastcancerrisk |