Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Dorling, Leila and Carvalho, Sara and Allen, Jamie and Parsons, Michael T. and Fortuno, Cristina and Gonzalez-Neira, Anna and Heijl, Stephan M. and Adank, Muriel A. and Ahearn, Thomas U. and Andrulis, Irene L. and Auvinen, Paivi and Becher, Heiko and Beckmann, Matthias W. and Behrens, Sabine and Bermisheva, Marina and Bogdanova, Natalia V. and Bojesen, Stig E. and Bolla, Manjeet K. and Bremer, Michael and Briceno, Ignacio and Camp, Nicola J. and Campbell, Archie and Castelao, Jose E. and Chang-Claude, Jenny and Chanock, Stephen J. and Chenevix-Trench, Georgia and Collee, J. Margriet and Czene, Kamila and Dennis, Joe and Dork, Thilo and Eriksson, Mikael and Evans, D. Gareth and Fasching, Peter A. and Figueroa, Jonine and Flyger, Henrik and Gabrielson, Marike and Gago-Dominguez, Manuela and Garcia-Closas, Montserrat and Giles, Graham G. and Glendon, Gord and Guenel, Pascal and Gundert, Melanie and Hadjisavvas, Andreas and Hahnen, Eric and Hall, Per and Hamann, Ute and Harkness, Elaine F. and Hartman, Mikael and Hogervorst, Frans B. L. and Hollestelle, Antoinette and Hoppe, Reiner and Howell, Anthony and Jakubowska, Anna and Jung, Audrey and Khusnutdinova, Elza and Kim, Sung-Won and Ko, Yon-Dschun and Kristensen, Vessela N. and Lakeman, Inge M. M. and Li, Jingmei and Lindblom, Annika and Loizidou, Maria A. and Lophatananon, Artitaya and Lubinski, Jan and Luccarini, Craig and Madsen, Michael J. and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Mavroudis, Dimitrios and Milne, Roger L. and Mohd Taib, Nur Aishah and Muir, Kenneth and Nevanlinna, Heli and Newman, William G. and Oosterwijk, Jan C. and Park, Sue K. and Peterlongo, Paolo and Radice, Paolo and Saloustros, Emmanouil and Sawyer, Elinor J. and Schmutzler, Rita K. and Shah, Mitul and Sim, Xueling and Southey, Melissa C. and Surowy, Harald and Suvanto, Maija and Tomlinson, Ian and Torres, Diana and Truong, Therese and van Asperen, Christi J. and Waltes, Regina and Wang, Qin and Yang, Xiaohong R. and Pharoah, Paul D. P. and Schmidt, Marjanka K. and Benitez, Javier and Vroling, Bas and Dunning, Alison M. and Teo, Soo Hwang and Kvist, Anders and de la Hoya, Miguel and Devilee, Peter and Spurdle, Amanda B. and Vreeswijk, Maaike P. G. and Easton, Douglas F. and Collaborators, NBCS and Investigators, KConFab and Investigators, SGBCC (2022) Breast cancer risks associated with missense variants in breast cancer susceptibility genes. Genome Medicine, 14 (1). ISSN 1756-994X, DOI

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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.

Item Type: Article
Funders: European Union (EU) (634935), European Union (EU) (633784), Wellcome Trust (v203477/Z/16/Z), Cancer Research UK (C1287/A16563)
Uncontrolled Keywords: Breast cancer; Genetic epidemiology; Risk prediction; Missense variants
Subjects: R Medicine
Divisions: Faculty of Medicine > Surgery Department
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 28 Aug 2023 04:03
Last Modified: 28 Aug 2023 04:03

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