Amendola et al. refine estimates of the burden of incidental (also known as secondary) findings that may be identified during the course of clinical exome sequencing studies. They searched the exome sequences of 4,300 European and 2,203 African ancestry participants in the NHLBI Exome Sequencing Project (ESP) for single-nucleotide variants (SNVs) in 112 genes, selected by a panel of expert reviewers to be associated with medically actionable genetic disorders that may remain undiagnosed in adults. They estimate that 2.0% of European and 1.1% of African ancestry participants would be returned results with actionable, highly penetrant pathogenic or likely pathogenic SNVs. The authors highlight continuing challenges in variant classification, including high rates (~53%) of discordant classification of the same variant by two independent reviewers. They stress the importance of using multiple data sources and reviewers, as well as the need for developing improved consensus criteria for pathogenicity classification and a curated variant interpretation knowledgebase.