Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience

Purpose To describe the frequency and nature of differences in variant classifications between clinicians and genetic testing laboratories. Methods Retrospective review of variants identified through genetic testing ordered in routine clinical care by clinicians in the Stanford Center for Inherited Cardiovascular Disease. We compared classifications made by clinicians, the testing laboratory, and other laboratories in ClinVar. Results Of 688 laboratory classifications, 124 (18%) differed from the clinicians’ classifications. Most differences in classification would probably affect clinical care of the patient and/or family (83%, 103/124). The frequency of discordant classifications differed depending on the testing laboratory ( P < 0.0001) and the testing laboratory’s classification ( P < 0.00001). For the majority (82/124, 66%) of discordant classifications, clinicians were more conservative (less likely to classify a variant pathogenic or likely pathogenic). The clinicians’ classification was discordant with one or more submitter in ClinVar in 49.1% (28/57) of cases, while the testing laboratory’s classification was discordant with a ClinVar submitter in 82.5% of cases (47/57, P = 0.0002). Conclusion The clinical team disagreed with the laboratory’s classification at a rate similar to that of reported disagreements between laboratories. Most of this discordance was clinically significant, with clinicians tending to be more conservative than laboratories in their classifications.