Clinical implications of conflicting variant interpretations in the cancer genetics clinic. Genetics in medicine : official journal of the American College of Medical Genetics Zukin, E., Culver, J. O., Liu, Y., Yang, Y., Ricker, C. N., Hodan, R., Sturgeon, D., Kingham, K., Chun, N. M., Rowe-Teeter, C., Singh, K., Zell, J. A., Ladabaum, U., McDonnell, K. J., Ford, J. M., Parmigiani, G., Braun, D., Kurian, A. W., Gruber, S. B., Idos, G. E. 2023: 100837


To describe the clinical impact of commercial laboratories issuing conflicting classifications of genetic variants.Results from 2,000 patients undergoing a multi-gene hereditary cancer panel by a single laboratory were analyzed. Clinically significant discrepancies between the lab provided test reports and other major commercial laboratories were identified, including differences between pathogenic/likely pathogenic (P/LP) and variant of uncertain significance (VUS) classifications, via review of ClinVar archives. For patients carrying a VUS, clinical documentation was assessed for evidence of provider awareness of the conflict.50/975 (5.1%) patients with non-negative results carried a variant with a clinically significant conflict, 19 with a P/LP variant reported in APC or MUTYH, and 31 with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. Only 10/28 (36%) patients with a VUS with a clinically significant conflict had a documented discussion by a provider about the conflict. Discrepant counseling strategies were utilized for different patients with the same variant. Among patients with a CDKN2A variant or a monoallelic MUTYH variant, providers were significantly more likely to make recommendations based on the laboratory-reported classification.Our findings highlight the frequency of variant interpretation discrepancies and importance of clinician awareness. Guidance is needed on managing patients with discrepant variants to support accurate risk assessment.

View details for DOI 10.1016/j.gim.2023.100837

View details for PubMedID 37057674