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%. 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).
We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS).
In 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.
The 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.
ACMG secondary findings; Familial cancer exome; Population study; Variant classification