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Human mutation DOI:10.1002/humu.22375

Large Numbers of Genetic Variants Considered to be Pathogenic are Common in Asymptomatic Individuals.

Publication TypeJournal Article
Year of Publication2013
AuthorsCassa, CA, Tong, MY, Jordan, DM
JournalHuman mutation
Date Published2013/07/01

It is now affordable to order clinically interpreted whole-genome sequence reports from clinical laboratories. One major component of these reports is derived from the knowledge base of previously identified pathogenic variants, including research articles, locus-specific, and other databases. While over 150,000 such pathogenic variants have been identified, many of these were originally discovered in small cohort studies of affected individuals, so their applicability to asymptomatic populations is unclear. We analyzed the prevalence of a large set of pathogenic variants from the medical and scientific literature in a large set of asymptomatic individuals (N = 1,092) and found 8.5% of these pathogenic variants in at least one individual. In the average individual in the 1000 Genomes Project, previously identified pathogenic variants occur on average 294 times (σ = 25.5) in homozygous form and 942 times (σ = 68.2) in heterozygous form. We also find that many of these pathogenic variants are frequently occurring: there are 3,744 variants with minor allele frequency (MAF) ≥ 0.01 (4.6%) and 2,837 variants with MAF ≥ 0.05 (3.5%). This indicates that many of these variants may be erroneous findings or have lower penetrance than previously expected.