Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

Purpose: We evaluated the Exome Aggregation Consortium (ExAC) database as a control cohort to classify variants across a diverse set of genes spanning dominant and recessively inherited disorders. Methods: The frequency of pathogenic variants in ExAC was compared with the estimated maximal pathogenic allele frequency (MPAF), based on the disease prevalence, penetrance, inheritance, allelic and locus heterogeneity of each gene. Additionally, the observed carrier frequency and the ethnicity-specific variant distribution were compared between ExAC and the published literature. Results: The carrier frequency and ethnic distribution of pathogenic variants in ExAC were concordant with reported estimates. Of 871 pathogenic/likely pathogenic variants across 19 genes, only 3 exceeded the estimated MPAF. Eighty-four percent of variants with ExAC frequencies above the estimated MPAF were classified as benign. Additionally, 20% of the cardiac and 19% of the Lynch syndrome gene variants originally classified as VUS occurred with ExAC frequencies above the estimated MPAF, making these suitable for reassessment. Conclusions: The ExAC database is a useful source for variant classification and is not overrepresented for pathogenic variants in the genes evaluated. However, the mutational spectrum, pseudogenes, genetic heterogeneity, and paucity of literature should be considered in deriving meaningful classifications using ExAC.