Legacy genetic testing results for cancer susceptibility: how common are conflicting classifications in a large variant dataset from multiple practices?
Yin K, Liu Y, Lamichhane B, Sandbach JF, Patel G, Compagnoni G, Kanak RH, Rosen B, Ondrula DP, Smith L, Brown E, Gold L, Whitworth P, App C, Euhus D, Semine A, Dwight Lyons S, Lazarte MAC, Parmigiani G, Braun D, Hughes KS. Legacy Genetic Testing Results for Cancer Susceptibility: How Common are Conflicting Classifications in a Large Variant Dataset from Multiple Practices? Ann Surg Oncol. 2020 Jul;27(7):2212-2220. doi: 10.1245/s10434-020-08492-9. Epub 2020 Apr 27. PMID: 32342295
PURPOSE: The classification of germline variants may differ between labs and change over time. We apply a variant harmonization tool, Ask2Me VarHarmonizer, to map variants to ClinVar and identify discordant variant classifications in a large multipractice variant dataset.
METHODS: A total of 7496 variants sequenced between 1996 and 2019 were collected from 11 clinical practices. Variants were mapped to ClinVar, and lab-reported and ClinVar variant classifications were analyzed and compared.
RESULTS: Of the 4798 unique variants identified, 3699 (77%) were mappable to ClinVar. Among mappable variants, variants of unknown significance (VUS) accounted for 74% of lab-reported classifications and 60% of ClinVar classifications. Lab-reported and ClinVar discordances were present in 783 unique variants (21.2% of all mappable variants); 121 variants (2.5% of all unique variants) had within-practice lab-reported discordances; and 56 variants (1.2% of all unique variants) had lab-reported discordances across practices. The unmappable variants were associated with a higher proportion of lab-reported pathogenic classifications (50% vs. 21%, p < 0.0001) and a lower proportion of lab-reported VUS classifications (46% vs. 74%, p < 0.0001).
CONCLUSIONS: Our study shows that discordant variant classification occurs frequently, which may lead to inappropriate recommendations for prophylactic treatments or clinical management.