Davidson, Aimee L. and Michailidou, Kyriaki and Parsons, Michael T. and Fortuno, Cristina and Bolla, Manjeet K. and Wang, Qin and Dennis, Joe and Naven, Marc and Abubakar, Mustapha and Ahearn, Thomas U. and Alonso, M. Rosario and Andrulis, Irene L. and Antoniou, Antonis C. and Auvinen, Paivi and Behrens, Sabine and Bermisheva, Marina A. and Bogdanova, Natalia and Bojesen, Stig E. and Bruning, Thomas and Byers, Helen J. and Camp, Nicola J. and Campbell, Archie and Castelao, Jose E. and Cessna, Melissa H. and Chang-Claude, Jenny and Chanock, Stephen J. and Chenevix-Trench, Georgia and Collee, J. Margriet and Czene, Kamila and Dork, Thilo and Eriksson, Mikael and Evans, D. Gareth and Fasching, Peter A. and Figueroa, Jonine D. and Flyger, Henrik and Gago-Dominguez, Manuela and Garcia-Closas, Montserrat and Glendon, Gord and Gonzalez-Neira, Anna and Grassmann, Felix and Gronwald, Jacek and Guenel, Pascal and Hadjisavvas, Andreas and Haeberle, Lothar and Hall, Per and Hamann, Ute and Hartman, Mikael and Ho, Peh Joo and Hooning, Maartje J. and Hoppe, Reiner and Howell, Anthony and Jakubowska, Anna and Khusnutdinova, Elza K. and Kristensen, Vessela N. and Li, Jingmei and Lim, Joanna and Lindblom, Annika and Liu, Jenny and Lophatananon, Artitaya and Mannermaa, Arto and Mavroudis, Dimitrios A. and Mensenkamp, Arjen R. and Milne, Roger L. and Muir, Kenneth R. and Newman, William G. and Obi, Nadia and Panayiotidis, Mihalis and Park, Sue K. and Park-Simon, Tjoung-Won and Peterlongo, Paolo and Radice, Paolo and Rashid, Muhammad U. and Rhenius, Valerie and Saloustros, Emmanouil and Sawyer, Elinor J. and Schmidt, Marjanka K. and Seibold, Petra and Shah, Mitul and Southey, Melissa C. and Teo, Soo Hwang and Tomlinson, Ian and Torres, Diana and Truong, Therese and van de Beek, Irma and van der Hout, Annemieke H. and Wendt, Camilla C. and Dunning, Alison M. and Pharoah, Paul D. P. and Devilee, Peter and Easton, Douglas F. and James, Paul A. and Spurdle, Amanda B. and Collaborators, NBCS and kConFab Investigators, - (2024) Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset. American Journal of Human Genetics, 111 (9). pp. 2059-2069. ISSN 0002-9297, DOI https://doi.org/10.1016/j.ajhg.2024.07.004.
Full text not available from this repository.Abstract
Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co- observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.
| Item Type: | Article |
|---|---|
| Funders: | United States Department of Health & Human Services National Institutes of Health (NIH) - USA (U24 5U24CA258058-02), National Breast Cancer Foundation, Australia (IIRS-21-102), National Health & Medical Research Council (NHMRC) of Australia (APP177524), European Union (EU) (634935), Saint Petersburg State University (PURE:103964756), Ministry Education and Science of Russian Federation (122041400169-2) |
| Subjects: | R Medicine > R Medicine (General) R Medicine > RC Internal medicine |
| Divisions: | Faculty of Medicine > Surgery Department |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 13 Feb 2025 01:47 |
| Last Modified: | 13 Feb 2025 01:47 |
| URI: | http://eprints.um.edu.my/id/eprint/47465 |
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