Abstract
BackgroundPrior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8–5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982).MethodsWe used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS).ResultsIn the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers.ConclusionThe 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.
Highlights
Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8–5%
Multiple studies using the newer pathogenicity scheme to investigate clinical exome sequencing data and publicly available sequence databases in primarily European-American and African-American cohorts have estimated the prevalence of ACMG SF gene list pathogenic/likely pathogenic (P/LP) variants to be approximately 0.8–5% [7, 8]
Demographics, and matching cases and controls For the entire Division of Cancer Epidemiology and Genetics (DCEG) Familial Exome cohort, exome sequencing was performed such that 88% of coding sequence from the University of California Santa Cruz (UCSC) human genome 19 transcripts database had ≥ 15 reads with an average coverage of 61×
Summary
Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8–5%. In 2013, the American College of Medical Genetics and Genomics (ACMG) recommended that “laboratories performing clinical [exome or genome] sequencing seek and report mutations of the specified classes or types” in a set of 56 genes associated with a severe phenotype, and for which disease risk may be reduced or managed before symptoms arise [1, 2]. These recommendations for reporting of incidental (or secondary) findings (SF) in clinical exome and genome sequencing were later amended to 59 genes (ACMG SF v2.0) [3]. The prevalence of P/LP variants in cancer cohorts remains largely uninvestigated, and to our knowledge, prevalence of P/LP variants has not been determined in a large cancer study with ethnicity-matched healthy controls
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