Clinical Implications of Conflicting Variant Interpretations in the Cancer Genetics Clinic

Various commercial laboratories are used in cancer genetics practice, which can lead to clinicians receiving reports with conflicting categorizations of genetic variants. Such discrepancies can have significant clinical implications and can potentially lead to different counseling approaches for different patients with the same variant. In this study, we describe the frequency of this occurrence, analyze genetics providers’ awareness of conflicting interpretations, and make comparisons of medical management recommendations provided to patients with discrepant classifications of the same variant. A cohort of 2,000 patients was recruited from three cancer genetics clinics from 2014 to 2016. All patients underwent the same hereditary cancer panel by one major commercial genetics laboratory. A review of ClinVar archives was performed to identify clinically significant conflicts between ClinVar and the test report, defined as either a variant of uncertain significance (VUS) on the test report with a pathogenic/likely pathogenic (P/LP) classification by major lab in ClinVar, or a P/LP variant on the test report with a VUS classification by a major lab in ClinVar. We demonstrate that 2.5% of patients had a variant with a clinically significant conflict in ClinVar when the test report was issued, including 19 patients with a P/LP variant reported in APC or MUTYH, and 31 patients with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. For patients with a VUS on their report who had a clinically significant conflict, analysis of available study case report forms and original results disclosure clinic notes revealed that only 10/28 (36%) of patients appeared to be counseled by a provider who was aware of the conflict. Patients in this cohort with clinically significant conflicts were then compared to patients outside the cohort who had been tested by the same providers utilizing different laboratories. A detailed case analysis led to the finding that discrepant counseling strategies were utilized for different patients with the same variant, within the same institution and even by the same counselor. The results of this study provide evidence that variant interpretation discrepancies have implications in medical management decisions. This highlights the importance of clinician awareness for possible conflicts in variant interpretation. Initiatives to harmonize variant classifications are critical to resolving discrepant interpretations and supporting clinicians in providing accurate risk assessment