Assessment of incidental findings in 232 whole exome sequences from the Baylor-Hopkins Center for Mendelian Genomics

PURPOSE: In March 2013, the ACMG published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing should be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole exome sequences from the Baylor-Hopkins Center for Mendelian Genomics. METHODS: We identified rare, nonsynonymous and splicing SNVs and indels and assessed variant classification using HGMD, Emory and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients. RESULTS: Our filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the 3 reference databases. Of 101 variants listed in HGMD, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86% of individuals had a reportable incidental variant. CONCLUSION: These observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.