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

J. Kim, W. Luo, M. Wang, T. Wegman-Ostrosky, M.N. Frone, J.J. Johnston, M.L. Nickerson, M. Rotunno, S.A. Li, M.I. Achatz, S.A. Brodie, M. Dean, K.C. De Andrade, F.P. Fortes, M. Gianferante, P. Khincha, M.L. McMaster, L.J. McReynolds, A. Pemov, M. PinheiroK.M. Santiago, B.P. Alter, N.E. Caporaso, S.M. Gadalla, L.R. Goldin, M.H. Greene, J. Loud, X.R. Yang, N.D. Freedman, S.M. Gapstur, M.M. Gaudet, D. Calista, P. Ghiorzo, M.C. Fargnoli, E. Nagore, K. Peris, S. Puig, M.T. Landi, B. Hicks, B. Zhu, J. Liu, J.N. Sampson, S.J. Chanock, L.J. Mirabello, L.M. Morton, L.G. Biesecker, M.A. Tucker, S.A. Savage, A.M. Goldstein, D.R. Stewart

Research output: Contribution to journalArticlepeer-review

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. © 2018 The Author(s).
Original languageEnglish
JournalGenome Medicine
Volume10
Issue number1
DOIs
Publication statusPublished - 2018

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