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

NBCS Collaborators, kConFab Investigators, L Dorling, S Carvalho, J Allen, MT Parsons, C Fortuno, A González-Neira, SM Heijl, MA Adank, TU Ahearn, IL Andrulis, P Auvinen, H Becher, Matthias W Beckmann, Sabine Behrens, Marina Bermisheva, Natalia V. Bogdanova, Stig E Bojesen, Manjeet K. BollaMichael Bremer, Ignacio Briceno, Nicola J. Camp, Archie Campbell, Jose E Castelao, Jenny Chang-Claude, Stephen J Chanock, Georgia Chenevix-Trench, J Margriet Collée, Kamila Czene, Joe Dennis, Thilo Dörk, Mikael Eriksson, D Gareth Evans, Peter A Fasching, Jonine Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago Dominguez, Montserrat García-Closas, Graham G. Giles, Gord Glendon, Pascal Guénel, Melanie Gündert, Andreas Hadjisavvas, Eric Hahnen, Per Hall, Ute Hamann, Elaine Harkness, Mikael Hartman, Frans B. L. Hogervorst, Antoinette Hollestelle, Reiner Hoppe, Tony Howell, Anna Jakubowska, Audrey Jung, Elza Khusnutdinova, Sung-Won Kim, Yon Dschun Ko, Vessela N. Kristensen, Inge M. M. Lakeman, Jingmei Li, Annika Lindblom, Maria A Loizidou, Artitaya Lophatananon, Jan Lubiński, Craig Luccarini, Michael J. Madsen, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Nur Aishah Mohd Taib, Kenneth Muir, Heli Nevanlinna, William Newman, Jan C Oosterwijk, Sue K Park, Paolo Peterlongo, Paolo Radice, Emmanouil Saloustros, Elinor J. Sawyer, Rita K Schmutzler, Mitul Shah, Xueling Sim, Melissa C Southey, Harald Surowy, Maija Suvanto, Ian Tomlinson, Diana Torres, Thérèse Truong, Christi J. Van Asperen, Regina Waltes, Qin Wang, Xiaohong R. Yang, Paul D.P. Pharoah, Marjanka K. Schmidt, Javier Benitez, Bas Vroling, Alison M. Dunning, Soo Hwang Teo, Anders Kvist, Miguel De la Hoya, Peter Devilee, Amanda B Spurdle, Maaike P G Vreeswijk, Douglas F Easton

Research output: Contribution to journalArticlepeer-review


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: Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), 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.
Original languageEnglish
Pages (from-to)1-36
Number of pages36
Publication statusPublished - 15 Sept 2021


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