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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

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

  2. Author Address

    NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA.NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Leidos Biomed Res Inc, Frederick, MD 21701 USA.Inst Nacl Cancerol, Div Invest, Mexico City 14080, DF, Mexico.NHGRI, Med Genom & Metab Genet Branch, Bethesda, MD 20892 USA.NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD 20877 USA.NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Rockville, MD 20850 USA.AC Camargo Canc Ctr, Int Res Ctr, BR-01508010 Sao Paulo, Brazil.NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA.NCI, Integrat Tumor Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA.NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA.Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA.Maurizio Bufalini Hosp, Dept Dermatol, Cesena, Italy.Univ Genoa & Genet Rare Canc, Dept Internal Med & Med Specialties, Osped Policin San Martino, IRCCS, Genoa, Italy.Univ Aquila, Dept Dermatol, Laquila, Italy.Inst Valenciano Oncol, Dept Dermatol, Valencia, Spain.Catholic Univ, Fdn Policlin Univ A Gemelli, Inst Dermatol, IRCCS, Rome, Italy.Univ Barcelona, Hosp Clin Barcelona, IDIBAPS, Melanoma Unit,Dermatol Dept, Barcelona, Spain.Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain.NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA.NCI, Off Director, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA.NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA.NCI, Div Canc Epidemiol & Genet, Human Genet Program, NIH, Rockville, MD 20850 USA.Hosp Sirio Libanes, Ctr Oncol, BR-01305005 Sao Paulo, Brazil.
    1. Year: 2018
    2. Date: Dec 24
    3. Epub Date: 2018 12 24
  2. Journal: Genome medicine
  3. BMC,
    1. 10
    2. 1
  5. Type of Article: Article
  6. Article Number: 99
  7. ISSN: 1756-994X
  1. 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 manualreview 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 30min; the first variant within a gene took significantly (p=0.0009) longer to review (median = 60min) compared with subsequent variants (median = 30min). 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.

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  2. DOI: 10.1186/s13073-018-0607-5
  3. PMID: 30583724
  4. PMCID: PMC6305568
  5. View record in Web of Science®
  6. WOS: 000454254400001

Library Notes

  1. Fiscal Year: FY2018-2019
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