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Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.
Davidson, A. L. ; Michailidou, K. ; Parsons, M. T. ; Fortuno, C. ; Bolla, M. K. ; Wang, Y.Extern* ; Dennis, J. ; Naven, M. ; Abubakar, M. ; Ahearn, T. U. ; Alonso, M. R. ; Andrulis, I. L. ; Antoniou, A. C. ; Auvinen, P. ; Behrens, S.DKFZ* ; Bermisheva, M. A. ; Bogdanova, N. V. ; Bojesen, S. E. ; Brüning, T. ; Byers, H. J. ; Camp, N. J. ; Campbell, A. ; Castelao, J. E. ; Cessna, M. H. ; Chang-Claude, J.DKFZ* ; Chanock, S. J. ; Chenevix-Trench, G. ; NBCS Collaborators (Collaboration Author) ; Collée, J. M. ; Czene, K. ; Dörk, T. ; Eriksson, M. ; Evans, D. G. ; Fasching, P. A. ; Figueroa, J. D. ; Flyger, H. ; Gago-Dominguez, M. ; García-Closas, M. ; Glendon, G. ; González-Neira, A. ; Grassmann, F. ; Gronwald, J. ; Guénel, P. ; Hadjisavvas, A. ; Haeberle, L. ; Hall, P. ; Hamann, U.DKFZ* ; Hartman, M. ; Ho, P. J. ; Hooning, M. J. ; Hoppe, R. ; Howell, A. ; Investigators, k. (Collaboration Author) ; Jakubowska, A. ; Khusnutdinova, E. K. ; Kristensen, V. N. ; Li, J. ; Lim, J. ; Lindblom, A. ; Liu, J. ; Lophatananon, A. ; Mannermaa, A. ; Mavroudis, D. A. ; Mensenkamp, A. R. ; Milne, R. L. ; Muir, K. R. ; Newman, W. G. ; Obi, N. ; Panayiotidis, M. I. ; Park, S. K. ; Park-Simon, T.-W. ; Peterlongo, P. ; Radice, P. ; Rashid, M. U. ; Rhenius, V. ; Saloustros, E. ; Sawyer, E. J. ; Schmidt, M. K. ; Seibold, P.DKFZ* ; Shah, M. ; Southey, M. C. ; Teo, S. H. ; Tomlinson, I. ; Torres, D.DKFZ* ; Truong, T. ; van de Beek, I. ; van der Hout, A. H. ; Wendt, C. C. ; Dunning, A. M. ; Pharoah, P. D. P. ; Devilee, P. ; Easton, D. F. ; James, P. A. ; Spurdle, A. B. ; Sahlberg, K. K. (Contributor) ; Børresen-Dale, A.-L. (Contributor) ; Gram, I. T. (Contributor) ; Olsen, K. S. (Contributor) ; Engebråten, O. (Contributor) ; Naume, B. (Contributor) ; Geisler, J. (Contributor) ; Osbreac (Contributor) ; Grenaker Alnæs, G. I. (Contributor) ; Amor, D. (Contributor) ; Andrews, L. (Contributor) ; Antill, Y. (Contributor) ; Balleine, R. (Contributor) ; Beesley, J. (Contributor) ; Bennett, I. (Contributor) ; Bogwitz, M. (Contributor) ; Bodek, S. (Contributor) ; Botes, L. (Contributor) ; Brennan, M. (Contributor) ; Brown, M. (Contributor) ; Buckley, M. (Contributor) ; Burke, J. (Contributor) ; Butow, P. (Contributor) ; Caldon, L. (Contributor) ; Campbell, I. (Contributor) ; Cao, M. (Contributor) ; Chakrabarti, A. (Contributor) ; Chauhan, D. (Contributor) ; Chauhan, M. (Contributor) ; Christian, A. (Contributor) ; Cohen, P. (Contributor) ; Colley, A. (Contributor) ; Crook, A. (Contributor) ; Cui, J. (Contributor) ; Courtney, E. (Contributor) ; Cummings, M. (Contributor) ; Dawson, S.-J. (Contributor) ; deFazio, A. (Contributor) ; Delatycki, M. (Contributor) ; Dickson, R. (Contributor) ; Dixon, J. (Contributor) ; Edwards, S. (Contributor) ; Farshid, G. (Contributor) ; Fellows, A. (Contributor) ; Fenton, G. (Contributor) ; Field, M. (Contributor) ; Flanagan, J. (Contributor) ; Fong, P. (Contributor) ; Forrest, L. (Contributor) ; Fox, S. (Contributor) ; French, J. (Contributor) ; Friedlander, M. (Contributor) ; Gaff, C. (Contributor) ; Gattas, M. (Contributor) ; George, P. (Contributor) ; Greening, S. (Contributor) ; Harris, M. (Contributor) ; Hart, S. (Contributor) ; Harraka, P. (Contributor) ; Hayward, N. (Contributor) ; Hopper, J. (Contributor) ; Hoskins, C. (Contributor) ; Hunt, C. (Contributor) ; Jenkins, M. (Contributor) ; Kidd, A. (Contributor) ; Kirk, J. (Contributor) ; Koehler, J. (Contributor) ; Kollias, J. (Contributor) ; Lakhani, S. (Contributor) ; Lawrence, M. (Contributor) ; Lee, J. (Contributor) ; Li, S. (Contributor) ; Lindeman, G. (Contributor) ; Lippey, J. (Contributor) ; Lipton, L. (Contributor) ; Lobb, L. (Contributor) ; Loi, S. (Contributor) ; Mann, G. (Contributor) ; Marsh, D. (Contributor) ; McLachlan, S. A. (Contributor) ; Meiser, B. (Contributor) ; Nightingale, S. (Contributor) ; O'Connell, S. (Contributor) ; O'Sullivan, S. (Contributor) ; Ortega, D. G. (Contributor) ; Pachter, N. (Contributor) ; Pang, J.-M. (Contributor) ; Pathak, G. (Contributor) ; Patterson, B. (Contributor) ; Pearn, A. (Contributor) ; Phillips, K. (Contributor) ; Pieper, E. (Contributor) ; Ramus, S. (Contributor) ; Rickard, E. (Contributor) ; Ragunathan, A. (Contributor) ; Robinson, B. (Contributor) ; Saleh, M. (Contributor) ; Skandarajah, A. (Contributor) ; Salisbury, E. (Contributor) ; Saunders, C. (Contributor) ; Saunus, J. (Contributor) ; Savas, P. (Contributor) ; Scott, R. (Contributor) ; Scott, C. (Contributor) ; Sexton, A. (Contributor) ; Shaw, J. (Contributor) ; Shelling, A. (Contributor) ; Srinivasa, S. (Contributor) ; Simpson, P. (Contributor) ; Taylor, J. (Contributor) ; Taylor, R. (Contributor) ; Thorne, H. (Contributor) ; Trainer, A. (Contributor) ; Tucker, K. (Contributor) ; Visvader, J. (Contributor) ; Walker, L. (Contributor) ; Williams, R. (Contributor) ; Winship, I. (Contributor) ; Young, M. A. (Contributor) ; Zaheed, M. (Contributor)
2024
Elsevier
New York, NY
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Please use a persistent id in citations: doi:10.1016/j.ajhg.2024.07.004
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.
Keyword(s): ACMG/AMP ; BP5 ; breast cancer ; co-observation ; genetics ; sequencing data ; variant classification
Note: 2024 Sep 5;111(9):2059-2069
Contributing Institute(s):
- C020 Epidemiologie von Krebs (C020)
- Molekulargenetik des Mammakarzinoms (B072)
Research Program(s):
- 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)
Appears in the scientific report
2024
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