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

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

Posted 15 Sep 2021
medRxiv DOI: 10.1101/2021.09.02.21262369

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.

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