Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0

16 Jan 2019 05:58 Ricerca


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

Inserito da segreteria SIDeMaST


Titolo originalePrevalence 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.
AutoriKim J, Luo W, Wang M, Wegman-Ostrosky T, Frone MN, Johnston JJ, Nickerson ML, Rotunno M, Li SA, Achatz MI, Brodie SA, Dean M, de Andrade KC, Fortes FP, Gianferante M, Khincha P, McMaster ML, McReynolds LJ, Pemov A, Pinheiro M, Santiago KM, Alter BP, Caporaso NE, Gadalla SM, Goldin LR, Greene MH, Loud J, Yang XR, Freedman ND, Gapstur SM, Gaudet MM, Calista D, Ghiorzo P, Fargnoli MC, Nagore E, Peris K, Puig S, Landi MT, Hicks B, Zhu B, Liu J, Sampson JN, Chanock SJ, Mirabello LJ, Morton LM, Biesecker LG, Tucker MA, Savage SA, Goldstein AM, Stewart DR.
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