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 ORCID: 0000-0002-3171-1556, Gago-Dominguez, Manuela, Garcia-Closas, Montserrat ORCID: 0000-0003-1033-2650, Giles, Graham G., Glendon, Gord, Guenel, Pascal ORCID: 0000-0002-8359-518X, Gundert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F., Hartman, Mikael, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hoppe, Reiner, Howell, Anthony, Jakubowska, Anna, Jung, Audrey ORCID: 0000-0003-0875-6673, Khusnutdinova, Elza, Kim, Sung-Won, Ko, Yon-Dschun, Kristensen, Vessela N., Lakeman, Inge M. M., Li, Jingmei ORCID: 0000-0001-8587-7511, 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 D. P., 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 P. G. and Easton, Douglas F. (2022). Breast cancer risks associated with missense variants in breast cancer susceptibility genes. Genome Med., 14 (1). LONDON: BMC. ISSN 1756-994X

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dorling, LeilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carvalho, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allen, JamieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parsons, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fortuno, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Neira, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heijl, Stephan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adank, Muriel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahearn, Thomas U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Auvinen, PaiviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becher, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckmann, Matthias W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behrens, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bermisheva, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bogdanova, Natalia V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bojesen, Stig E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolla, Manjeet K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bremer, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Briceno, IgnacioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Camp, Nicola J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, ArchieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Castelao, Jose E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chang-Claude, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chanock, Stephen J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collee, J. MargrietUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Czene, KamilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dennis, JoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dork, ThiloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eriksson, MikaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, D. GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fasching, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figueroa, JonineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flyger, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabrielson, MarikeUNSPECIFIEDorcid.org/0000-0002-3171-1556UNSPECIFIED
Gago-Dominguez, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Closas, MontserratUNSPECIFIEDorcid.org/0000-0003-1033-2650UNSPECIFIED
Giles, Graham G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glendon, GordUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenel, PascalUNSPECIFIEDorcid.org/0000-0002-8359-518XUNSPECIFIED
Gundert, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hadjisavvas, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hall, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harkness, Elaine F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartman, MikaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hogervorst, Frans B. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hollestelle, AntoinetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, ReinerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Howell, AnthonyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jung, AudreyUNSPECIFIEDorcid.org/0000-0003-0875-6673UNSPECIFIED
Khusnutdinova, ElzaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Sung-WonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ko, Yon-DschunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kristensen, Vessela N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lakeman, Inge M. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, JingmeiUNSPECIFIEDorcid.org/0000-0001-8587-7511UNSPECIFIED
Lindblom, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loizidou, Maria A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lophatananon, ArtitayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lubinski, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luccarini, CraigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madsen, Michael J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mannermaa, ArtoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manoochehri, MehdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Margolin, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mavroudis, DimitriosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milne, Roger L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohd Taib, Nur AishahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muir, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Newman, William G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oosterwijk, Jan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, Sue K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saloustros, EmmanouilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sawyer, Elinor J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, MitulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sim, XuelingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, Melissa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Surowy, HaraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suvanto, MaijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomlinson, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torres, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Truong, ThereseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Asperen, Christi J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waltes, ReginaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, QinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, Xiaohong R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pharoah, Paul D. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Marjanka K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vroling, BasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dunning, Alison M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Soo HwangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kvist, AndersUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de la Hoya, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devilee, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vreeswijk, Maaike P. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-699579
DOI: 10.1186/s13073-022-01052-8
Journal or Publication Title: Genome Med.
Volume: 14
Number: 1
Date: 2022
Publisher: BMC
Place of Publication: LONDON
ISSN: 1756-994X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UNKNOWN CLINICAL-SIGNIFICANCE; SEQUENCE VARIANTS; PATHOGENICITY; CLASSIFICATION; SUBSTITUTIONS; MUTATIONS; FRAMEWORK; BRCA1Multiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69957

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