Background This study aimed to identify and resolve discordant variant interpretations across clinical molecular genetic laboratories through the Canadian Open Genetics Repository (COGR), an online collaborative effort for variant sharing and interpretation.
Methods Laboratories uploaded variant data to the Franklin Genoox platform. Reports were issued to each laboratory, summarising variants where conflicting classifications with another laboratory were noted. Laboratories could then reassess variants to resolve discordances. Discordance was calculated using a five-tier model (pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), benign (B)), a three-tier model (LP/P are positive, VUS are inconclusive, LB/B are negative) and a two-tier model (LP/P are clinically actionable, VUS/LB/B are not). We compared the COGR classifications to automated classifications generated by Franklin.
Results Twelve laboratories submitted classifications for 44 510 unique variants. 2419 variants (5.4%) were classified by two or more laboratories. From baseline to after reassessment, the number of discordant variants decreased from 833 (34.4% of variants reported by two or more laboratories) to 723 (29.9%) based on the five-tier model, 403 (16.7%) to 279 (11.5%) based on the three-tier model and 77 (3.2%) to 37 (1.5%) based on the two-tier model. Compared with the COGR classification, the automated Franklin classifications had 94.5% sensitivity and 96.6% specificity for identifying actionable (P or LP) variants.
Conclusions The COGR provides a standardised mechanism for laboratories to identify discordant variant interpretations and reduce discordance in genetic test result delivery. Such quality assurance programmes are important as genetic testing is implemented more widely in clinical care.
- human genetics
- genetic testing
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Collaborators Canadian Open Genetics Repository Working Group: Ron Agatep, Peter Ainsworth, Mohammad R Akbari, Melyssa Aronson, Raveen Basran, Andre Blavier, Andrea Blumenthal, Yvonne Bombard, Ian Bosdet, Kym Boycott, Michael Brudno, Kathleen Buckley, Jodi Campbell, Philippe M Campeau, Melanie Care, Nancy Carson, Martin C Chang, Ronald Carter, George Charames, David Chitayat, George Chong, Edmond Chouinard, Kathy Chun, Kenneth J Craddock, Vanessa Di Gioacchino, Rod Docking, Andrea Eisen, Hanna Faghfoury, Sandra Farrell, Harriet Feilotter, Bridget Fernandez, Marc Fiume, Cynthia Forster-Gibson, Jan Friedman, William Foulkes, Peter Goodhand, Robert Hegele, Spring Holter, Sheri Horsburgh, Lauren Hughes, Stacey Hume, Olga Jarinova, Anne Junker, Aly Karsan, Sam Khalouei, Raymond H Kim, Joan Knoll, Elena Kolomietz, Bartha Knoppers, Ryan Lamont, Matthew Lebo, Jordan Lerner-Ellis, Georges Maire, Christian Marshall, Elizabeth McCready, Grant Mitchell, Chantal Morel, Tanya Nelson, Abdul Noor, Brian O’Connor, Darren O’Rielly, Francis Ouellette, Jillian Parboosingh, Trevor Pugh, Hilary Racher, Heidi Rehm, Christie Riddell, Jean-Baptiste Riviere, David S Rosenblatt, Guy Rouleau, Andrea Ruchon, Peter Sabatini, Bekim Sadikovic, Kara Semotiuk, Stephen W Scherer, Cheryl Shuman, Josh Silver, Katherine Siminovitch, Lesley Solomon-Izsak, Jean-Francois Soucy, Marsha Speevak, James Stavropoulos, Lincoln Stein, Sherryl Taylor, Deborah Terespolsky, Robert Tomaszewski, Tracy Tucker, Richard F Wintle, Nora Wong, Marina Wang, Nicholas Watkins, John S Waye, Shana White, Michael O Woods, Philip Wyatt, Sean Young, Kathleen-Rose Zakoor.
Contributors Conceptualisation: JL-E, MSL. Formal analysis: CM. Funding acquisition: JL-E, MSL. Investigation: CM, ACS, JM, RT, ST, SH, RA, ES, HF, LS, HW, LLdlV, CRM, MMA, TS, GSC, VDG, NW, WDF, MC, NH, GC, REL, JP, AK, IB, SSY, TT, MRA, MS, AKV, MSL, JL-E. Methodology: JL-E. Project Administration: JL-E, CM. Resources: ACS, JM, RT, ST, SH, RA, ES, HF, LS, HW, LLdlV, CRM, MMA, TS, GSC, VDG, NW, WDF, MC, NH, GC, RL, JP, AK, IB, SSY, TT, MA, MDS, AKV, MSL, JL-E. Supervision: JL-E. Writing—original draft: CM, JL-E. Writing—review and editing: JL-E, CM, LLdlV, WDF, VDG, TT, TS, HEF, AKV, ES, CRM, MMA.
Funding This work was funded by the government of Canada through Genome Canada, the Ontario Genomics Institute (OGI-070) and Can-SHARE. The Can-SHARE project was supported by Genome Quebec; Genome Canada; the government of Canada; the Ministère de l’Économie, Innovation et Exportation du Québec and the Canadian Institutes of Health Research (fund 141210). This work was supported by the Canadian provincial genetic testing programs and their Ministries of Health as well as the laboratory directors and staff.
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Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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