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

2024; Elsevier BV; Volume: 111; Issue: 9 Linguagem: Inglês

10.1016/j.ajhg.2024.07.004

1537-6605

Aimee L. Davidson, Kyriaki Michailidou, Michael T. Parsons, Cristina Fortuño, 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 Bermisheva, Natalia Bogdanova, Stig E. Bojesen, Thomas Brüning, Helen Byers, Nicola J. Camp, Archie Campbell, Jose E. Castelao, Melissa H. Cessna, Jenny C. Chang, Stephen J. Chanock, Georgia Chenevix‐Trench, Kristine Kleivi Sahlberg, Anne‐Lise Børresen‐Dale, Inger Torhild Gram, Karina Standahl Olsen, Olav Engebråten, Bjørn Naume, Jürgen Geisler, OSBREAC, Grethe I.G. 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 J. Amor, Lesley Andrews, Yoland Antill, Rosemary L. Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Simon Bodek, Leon Botes, Meagan Brennan, Matthew A. Brown, Michael F. Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Alice Christian, Paul A. Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret C. Cummings, Sarah‐Jane Dawson, Anna deFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Stacey L. Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James M. Flanagan, Peter C.C. Fong, Laura Forrest, Stephen Fox, Juliet D. French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter M. George, Sian Greening, Marion Harris, Stewart Hart, Philip Harraka, Nicholas K. Hayward, John L. Hopper, Cass Hoskins, Clare Hunt, Mark A. Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil R. Lakhani, Mitchell Lawrence, Jason S. Lee, Shuai Li, Geoffrey J. Lindeman, Jocelyn Lippey, Lara Lipton, Liz Lobb, Sherene Loi, Graham J. Mann, Deborah J. 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‐Anne Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Abi Ragunathan, Bridget A. Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi M. Saunus, Peter Savas, Rodney J. Scott, Clare L. Scott, Adrienne Sexton, Joanne Shaw, Andrew N. Shelling, Shweta Srinivasa, Peter Simpson, Jessica Taylor, Renea A. Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan C. Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, Milita Zaheed, Anna Jakubowska, Э. К. Хуснутдинова, Vessela N. Kristensen, Jingmei Li, Joanna Lim, Annika Lindblom, Jenny Liu, Artitaya Lophatananon, Arto Mannermaa, D. Mavroudis, Arjen R. Mensenkamp, Roger L. Milne, Kenneth Muir, William G. Newman, Nadia Obi, Mihalis I. Panayiotidis, Sue K. Park, Tjoung‐Won Park‐Simon, Paolo Peterlongo, Paolo Radice, Muhammad Usman 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,

Cancer Genomics and Diagnostics

Summary 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.