Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls.

Kim J1, Luo W2, Wang M2, Wegman-Ostrosky T1,3, Frone MN1, Johnston JJ4, Nickerson ML5, Rotunno M6, Li SA2, Achatz MI1,7, Brodie SA2, Dean M5, de Andrade KC1,8, Fortes FP1,8, Gianferante M1, Khincha P1, McMaster ML1, McReynolds LJ1, Pemov A1, Pinheiro M1, Santiago KM1,8, Alter BP1, Caporaso NE9, Gadalla SM1, Goldin LR10, Greene MH1, Loud J1, Yang XR10, Freedman ND11, Gapstur SM12, Gaudet MM12, Calista D13, Ghiorzo P14, Fargnoli MC15, Nagore E16, Peris K17, Puig S18, Landi MT10, Hicks B2, Zhu B2, Liu J2, Sampson JN19, Chanock SJ20, Mirabello LJ1, Morton LM21, Biesecker LG4, Tucker MA22, Savage SA1, Goldstein AM23, Stewart DR24.

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Abstract

BACKGROUND:

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).

METHODS:

We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS).

RESULTS:

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.

CONCLUSION:

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.