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https://doi.org/10.1186/s13073-022-01052-8
Title: | Breast cancer risks associated with missense variants in breast cancer susceptibility genes | Authors: | Dorling, Leila Carvalho, Sara Allen, Jamie Parsons, Michael T Fortuno, Cristina Gonzalez-Neira, Anna Heijl, Stephan M Adank, Muriel A Ahearn, Thomas U Andrulis, Irene L Auvinen, Paivi Becher, Heiko Beckmann, Matthias W Behrens, Sabine Bermisheva, Marina Bogdanova, Natalia V Bojesen, Stig E Bolla, Manjeet K Bremer, Michael Briceno, Ignacio Camp, Nicola J Campbell, Archie Castelao, Jose E Chang-Claude, Jenny Chanock, Stephen J Chenevix-Trench, Georgia Collee, J Margriet Czene, Kamila Dennis, Joe Dork, Thilo Eriksson, Mikael Evans, D Gareth Fasching, Peter A Figueroa, Jonine Flyger, Henrik Gabrielson, Marike Gago-Dominguez, Manuela Garcia-Closas, Montserrat Giles, Graham G Glendon, Gord Guenel, Pascal Gundert, Melanie Hadjisavvas, Andreas Hahnen, Eric Hall, Per Hamann, Ute Harkness, Elaine F Hartman, Mikael Hogervorst, Frans BL Hollestelle, Antoinette Hoppe, Reiner Howell, Anthony Jakubowska, Anna Jung, Audrey Khusnutdinova, Elza Kim, Sung-Won Ko, Yon-Dschun Kristensen, Vessela N Lakeman, Inge MM Li, Jingmei Lindblom, Annika Loizidou, Maria A Lophatananon, Artitaya Lubinski, Jan Luccarini, Craig Madsen, Michael J Mannermaa, Arto Manoochehri, Mehdi Margolin, Sara Mavroudis, Dimitrios Milne, Roger L Mohd Taib, Nur Aishah Muir, Kenneth Nevanlinna, Heli Newman, William G Oosterwijk, Jan C Park, Sue K Peterlongo, Paolo Radice, Paolo Saloustros, Emmanouil Sawyer, Elinor J Schmutzler, Rita K Shah, Mitul Sim, Xueling Southey, Melissa C Surowy, Harald Suvanto, Maija Tomlinson, Ian Torres, Diana Truong, Therese van Asperen, Christi J Waltes, Regina Wang, Qin Yang, Xiaohong R Pharoah, Paul DP Schmidt, Marjanka K Benitez, Javier Vroling, Bas Dunning, Alison M Teo, Soo Hwang Kvist, Anders de la Hoya, Miguel Devilee, Peter Spurdle, Amanda B Vreeswijk, Maaike PG Easton, Douglas F |
Keywords: | Science & Technology Life Sciences & Biomedicine Genetics & Heredity Breast cancer Genetic epidemiology Risk prediction Missense variants UNKNOWN CLINICAL-SIGNIFICANCE SEQUENCE VARIANTS PATHOGENICITY CLASSIFICATION SUBSTITUTIONS MUTATIONS FRAMEWORK BRCA1 |
Issue Date: | 18-May-2022 | Publisher: | BMC | Citation: | Dorling, Leila, Carvalho, Sara, Allen, Jamie, Parsons, Michael T, Fortuno, Cristina, Gonzalez-Neira, Anna, Heijl, Stephan M, Adank, Muriel A, Ahearn, Thomas U, Andrulis, Irene L, Auvinen, Paivi, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bremer, Michael, Briceno, Ignacio, Camp, Nicola J, Campbell, Archie, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Collee, J Margriet, Czene, Kamila, Dennis, Joe, Dork, Thilo, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Garcia-Closas, Montserrat, Giles, Graham G, Glendon, Gord, Guenel, Pascal, Gundert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hartman, Mikael, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoppe, Reiner, Howell, Anthony, Jakubowska, Anna, Jung, Audrey, Khusnutdinova, Elza, Kim, Sung-Won, Ko, Yon-Dschun, Kristensen, Vessela N, Lakeman, Inge MM, Li, Jingmei, Lindblom, Annika, Loizidou, Maria A, Lophatananon, Artitaya, Lubinski, Jan, Luccarini, Craig, Madsen, Michael J, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L, Mohd Taib, Nur Aishah, Muir, Kenneth, Nevanlinna, Heli, Newman, William G, Oosterwijk, Jan C, Park, Sue K, Peterlongo, Paolo, Radice, Paolo, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Shah, Mitul, Sim, Xueling, Southey, Melissa C, Surowy, Harald, Suvanto, Maija, Tomlinson, Ian, Torres, Diana, Truong, Therese, van Asperen, Christi J, Waltes, Regina, Wang, Qin, Yang, Xiaohong R, Pharoah, Paul DP, Schmidt, Marjanka K, Benitez, Javier, Vroling, Bas, Dunning, Alison M, Teo, Soo Hwang, Kvist, Anders, de la Hoya, Miguel, Devilee, Peter, Spurdle, Amanda B, Vreeswijk, Maaike PG, Easton, Douglas F (2022-05-18). Breast cancer risks associated with missense variants in breast cancer susceptibility genes. GENOME MEDICINE 14 (1). ScholarBank@NUS Repository. https://doi.org/10.1186/s13073-022-01052-8 | Abstract: | Background: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility. | Source Title: | GENOME MEDICINE | URI: | https://scholarbank.nus.edu.sg/handle/10635/237389 | ISSN: | 1756-994X | DOI: | 10.1186/s13073-022-01052-8 |
Appears in Collections: | Staff Publications Elements |
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