Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset

Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset

The American Journal of Human Genetics

10.1016/j.ajhg.2024.07.004

https://doi.org/10.1016/j.ajhg.2024.07.004

Aimee L. Davidson, Kyriaki Michailidou, Michael T. Parsons, Cristina Fortuno, Manjeet K. Bolla, Qin Wang, Joe Dennis, Marc Naven, Mustapha Abubakar, Thomas U. Ahearn, M. Rosario Alonso, Irene L. Andrulis, Antonis C. Antoniou, Päivi Auvinen, Sabine Behrens, Marina A. Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Thomas Brüning, Helen J. Byers, Nicola J. Camp, Archie Campbell, Jose E. Castelao, Melissa H. Cessna, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Kristine K. Sahlberg, Anne-Lise Børresen-Dale, Inger Torhild Gram, Karina Standahl Olsen, Olav Engebråten, Bjørn Naume, Jürgen Geisler, OSBREAC, Grethe I. Grenaker Alnæs, J. Margriet Collée, Kamila Czene, Thilo Dörk, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Gord Glendon, Anna González-Neira, Felix Grassmann, Jacek Gronwald, Pascal Guénel, Andreas Hadjisavvas, Lothar Haeberle, Per Hall, Ute Hamann, Mikael Hartman, Peh Joo Ho, Maartje J. Hooning, Reiner Hoppe, Anthony Howell, David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Simon Bodek, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret Cummings, Sarah-Jane Dawson, Anna deFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Philip Harraka, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoff Lindeman, Jocelyn Lippey, Lara Lipton, Liz Lobb, Sherene Loi, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Jia-Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Abi Ragunathan, Bridget Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Peter Savas, Rodney Scott, Clare Scott, Adrienne Sexton, Joanne Shaw, Andrew Shelling, Shweta Srinivasa, Peter Simpson, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, Milita Zaheed, Anna Jakubowska, Elza K. Khusnutdinova, Vessela N. Kristensen, Jingmei Li, Joanna Lim, Annika Lindblom, Jenny Liu, Artitaya Lophatananon, Arto Mannermaa, Dimitrios A. Mavroudis, Arjen R. Mensenkamp, Roger L. Milne, Kenneth R. Muir, William G. Newman, Nadia Obi, Mihalis I. Panayiotidis, Sue K. Park, Tjoung-Won Park-Simon, Paolo Peterlongo, Paolo Radice, Muhammad U. Rashid, Valerie Rhenius, Emmanouil Saloustros, Elinor J. Sawyer, Marjanka K. Schmidt, Petra Seibold, Mitul Shah, Melissa C. Southey, Soo Hwang Teo, Ian Tomlinson, Diana Torres, Thérèse Truong, Irma van de Beek, Annemieke H. van der Hout, Camilla C. Wendt, Alison M. Dunning, Paul D.P. Pharoah, Peter Devilee, Douglas F. Easton, Paul A. James, Amanda B. Spurdle

02 August 2024

Davidson AL, Michailidou K, Parsons MT, Fortuno C, Bolla MK, Wang Q, Dennis J, Naven M, Abubakar M, Ahearn TU, Alonso MR, Andrulis IL, Antoniou AC, Auvinen P, Behrens S, Bermisheva MA, Bogdanova NV, Bojesen SE, Brüning T, Byers HJ, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chang-Claude J, Chanock SJ, Chenevix-Trench G; NBCS Collaborators; Collée JM, Czene K, Dörk T, Eriksson M, Evans DG, Fasching PA, Figueroa JD, 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, Hartman M, Ho PJ, Hooning MJ, Hoppe R, Howell A; kConFab Investigators; Jakubowska A, Khusnutdinova EK, Kristensen VN, Li J, Lim J, Lindblom A, Liu J, Lophatananon A, Mannermaa A, Mavroudis DA, Mensenkamp AR, Milne RL, Muir KR, Newman WG, Obi N, Panayiotidis MI, Park SK, Park-Simon TW, Peterlongo P, Radice P, Rashid MU, Rhenius V, Saloustros E, Sawyer EJ, Schmidt MK, Seibold P, Shah M, Southey MC, Teo SH, Tomlinson I, Torres D, Truong T, van de Beek I, van der Hout AH, Wendt CC, Dunning AM, Pharoah PDP, Devilee P, Easton DF, James PA, Spurdle AB. Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset. Am J Hum Genet. 2024 Sep 5;111(9):2059-2069. doi: 10.1016/j.ajhg.2024.07.004. Epub 2024 Aug 2. PMID: 39096911; PMCID: PMC11393698.

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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

There was no specific funding for the research done

https://oar.a-star.edu.sg/communities-collections/articles/22632

0002-9297

Genome Institute of Singapore