Reassessment of Genomic Sequence Variation to Harmonize Interpretation for Personalized Medicine

Abstract

Accurate interpretation of DNA sequence variation is a prerequisite for implementing personalized medicine. Discrepancies in interpretation between testing laboratories impede the effective use of genetic test results in clinical medicine. To better understand the underpinnings of these discrepancies, we quantified differences in variant classification internally over time and those between our diagnostic laboratory and other laboratories and resources. We assessed the factors that contribute to these discrepancies and those that facilitate their resolution. Our process resolved 72% of nearly 300 discrepancies between pairs of laboratories to within a one-step classification difference and identified key sources of data that facilitate changes in variant interpretation. The identification and harmonization of variant discrepancies will maximize the clinical use of genetic information; these processes will be fostered by the accumulation of additional population data as well as the sharing of data between diagnostic laboratories.

Figure 1

Comparisons Used for Identifying Sources of Variant Discrepancies Sequence variants identified through molecular testing at the EGL were captured in our internal variant database, EmVar. We quantified gene and variant classifications internally in comparison to those in the popular human genetics databases, such as GeneReviews, OMIM, HGMD, locus-specific databases, and other disease-specific databases, as well as population databases, such as dbSNP, the EVS, and the ExAC Browser (1). We assessed changes in variant classification internally over time (2). Finally, we identified and attempted to rectify variant-classification discrepancies between the EGL and other clinical genetic-testing laboratories (3).