Article|Articles in Press, 100837

Clinical implications of conflicting variant interpretations in the cancer genetics clinic

Published:April 10, 2023DOI:
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      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.



      June 8, 2023

      June 2023 - The clinical impact of commercial laboratories issuing conflicting classifications of genetic variants – are some clinicians unknowingly diagnosing in the dark?

      Labs that conduct genetic testing typically return the interpretations of reportable variants, the results of those tests, to clinicians. And while there are guidelines for such tests, discrepancies in interpretation of genetic variants from one lab to another can still occur. In a recent study in Genetics in Medicine, a team of researchers analyzed the data from 2000 patients undergoing genetic testing for hereditary cancers at three different cancer centers in order to determine the extent of such discrepancies, and whether or not clinicians were aware of them. Elyssa Zukin, MS, genetic counselor at City of Hope, a cancer research and treatment organization, and Gregory Idos, MD, a gastroenterologist and cancer geneticist at City of Hope, joined GenePod to discuss the results.

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