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

Ketty Peris, Maria Concetta Fargnoli, Jung Kim, Wen Luo, Mingyi Wang, Talia Wegman-Ostrosky, Megan N. Frone, Jennifer J. Johnston, Michael L. Nickerson, Melissa Rotunno, Shengchao A. Li, Maria I. Achatz, Seth A. Brodie, Michael Dean, Kelvin C. De Andrade, Fernanda P. Fortes, Matthew Gianferante, Payal Khincha, Mary L. Mcmaster, Lisa J. McreynoldsAlexander Pemov, Maisa Pinheiro, Karina M. Santiago, Blanche P. Alter, Neil E. Caporaso, Shahinaz M. Gadalla, Lynn R. Goldin, Mark H. Greene, Jennifer Loud, Xiaohong R. Yang, Neal D. Freedman, Susan M. Gapstur, Mia M. Gaudet, Donato Calista, Paola Ghiorzo, Eduardo Nagore, Susana Puig, Maria Teresa Landi, Belynda Hicks, Bin Zhu, Jia Liu, Joshua N. Sampson, Stephen J. Chanock, Lisa J. Mirabello, Lindsay M. Morton, Leslie G. Biesecker, Margaret A. Tucker, Sharon A. Savage, Alisa M. Goldstein, Douglas R. Stewart

Risultato della ricerca: Contributo in rivistaArticolo in rivista

6 Citazioni (Scopus)


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.
Lingua originaleEnglish
pagine (da-a)99-N/A
RivistaGenome Medicine
Stato di pubblicazionePubblicato - 2018


  • ACMG secondary findings
  • Aged
  • Cohort Studies
  • DNA Mutational Analysis
  • Ethnic Groups
  • Familial cancer exome
  • Female
  • Genes, Neoplasm
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mutation
  • Neoplasms
  • Polymorphism, Single Nucleotide
  • Population study
  • Variant classification


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