Please use this identifier to cite or link to this item: 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
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