pathogenic variant burden in the exac database an empirical approach to evaluating population data for clinical variant interpretation background the frequency of a variant in the general population is a key criterion used in the clinical interpretation of sequence variants with certain exceptions such as founder mutations the rarity of a variant is a prerequisite for pathogenicity however defining the threshold at which a variant should be considered too common is challenging and therefore diagnostic laboratories have typically set conservative allele frequency thresholdsmethods recent publications of large population sequencing data such as the exome aggregation consortium exac database provide an opportunity to characterize with accuracy and precision the frequency distributions of very rare diseasecausing alleles allele frequencies of pathogenic variants in clinvar as well as variants expected to be pathogenic through the nonsensemediated decay nmd pathway were analyzed to study the burden of pathogenic variants in 79 genes of clinical importanceresults of 1364 brca1 and brca2 variants that are well characterized as pathogenic or that are expected to lead to nmd 1350 variants had an allele frequency of less than 00025 the remaining 14 variants were previously published founder mutations importantly we observed no difference in the distributions of pathogenic variants expected to be lead to nmd compared to those that are not therefore we expanded the analysis to examine the distributions of nmd expected variants in 77 additional genes these 77 genes were selected to represent a broad set of clinical areas modes of inheritance and penetrance among these variants most 973 had an allele frequency of less than 001 furthermore pathogenic variants with allele frequencies greater than 001 were well characterized in publications and included many founder mutationsconclusions the observations made in this study suggest that with certain caveats a very low allele frequency threshold can be adopted to more accurately interpret sequence variants