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.

Kim, J., Luo, W., Wang, M., Wegman-Ostrosky, T., Frone, M. N., Johnston, J. J., Nickerson, M. L., Rotunno, M., Li, S. A., Achatz, M. I., Brodie, S. A., Dean, M., De Andrade, K. C., Fortes, F. P., Gianferante, M., Khincha, P., Mcmaster, M. L., Mcreynolds, L. J., Pemov, A., Pinheiro, M., Santiago, K. M., Alter, B. P., Caporaso, N. E., Gadalla, S. M., Goldin, L. R., Greene, M. H., Loud, J., Yang, X. R., Freedman, N. D., Gapstur, S. M., Gaudet, M. M., Calista, D., Ghiorzo, P., Fargnoli, M. C., Nagore, E., Peris, K., Puig, S., Landi, M. T., Hicks, B., Zhu, B., Liu, J., Sampson, J. N., Chanock, S. J., Mirabello, L. J., Morton, L. M., Biesecker, L. G., Tucker, M. A., Savage, S. A., Goldstein, A. M., Stewart, D. R., 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, <<GENOME MEDICINE>>, 2018; 10 (1): 99-N/A. [doi:10.1186/s13073-018-0607-5] [http://hdl.handle.net/10807/167432]

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

Fargnoli, Maria Concetta;Peris, Ketty;
2018

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
Inglese
Kim, J., Luo, W., Wang, M., Wegman-Ostrosky, T., Frone, M. N., Johnston, J. J., Nickerson, M. L., Rotunno, M., Li, S. A., Achatz, M. I., Brodie, S. A., Dean, M., De Andrade, K. C., Fortes, F. P., Gianferante, M., Khincha, P., Mcmaster, M. L., Mcreynolds, L. J., Pemov, A., Pinheiro, M., Santiago, K. M., Alter, B. P., Caporaso, N. E., Gadalla, S. M., Goldin, L. R., Greene, M. H., Loud, J., Yang, X. R., Freedman, N. D., Gapstur, S. M., Gaudet, M. M., Calista, D., Ghiorzo, P., Fargnoli, M. C., Nagore, E., Peris, K., Puig, S., Landi, M. T., Hicks, B., Zhu, B., Liu, J., Sampson, J. N., Chanock, S. J., Mirabello, L. J., Morton, L. M., Biesecker, L. G., Tucker, M. A., Savage, S. A., Goldstein, A. M., Stewart, D. R., 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, <<GENOME MEDICINE>>, 2018; 10 (1): 99-N/A. [doi:10.1186/s13073-018-0607-5] [http://hdl.handle.net/10807/167432]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/167432
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