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 journalArticle

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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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. / 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.

In: Genome Medicine, Vol. 10, No. 1, 2018.

Research output: Contribution to journalArticle

Kim, 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 2018, '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, vol. 10, no. 1. https://doi.org/10.1186/s13073-018-0607-5
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. In: Genome Medicine. 2018 ; Vol. 10, No. 1.
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title = "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",
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. {\circledC} 2018 The Author(s).",
author = "J. Kim and W. Luo and M. Wang and T. Wegman-Ostrosky and M.N. Frone and J.J. Johnston and M.L. Nickerson and M. Rotunno and S.A. Li and M.I. Achatz and S.A. Brodie and M. Dean and {De Andrade}, K.C. and F.P. Fortes and M. Gianferante and P. Khincha and M.L. McMaster and L.J. McReynolds and A. Pemov and M. Pinheiro and K.M. Santiago and B.P. Alter and N.E. Caporaso and S.M. Gadalla and L.R. Goldin and M.H. Greene and J. Loud and X.R. Yang and N.D. Freedman and S.M. Gapstur and M.M. Gaudet and D. Calista and P. Ghiorzo and M.C. Fargnoli and E. Nagore and K. Peris and S. Puig and M.T. Landi and B. Hicks and B. Zhu and J. Liu and J.N. Sampson and S.J. Chanock and L.J. Mirabello and L.M. Morton and L.G. Biesecker and M.A. Tucker and S.A. Savage and A.M. Goldstein and D.R. Stewart",
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TY - JOUR

T1 - 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

AU - Kim, J.

AU - Luo, W.

AU - Wang, M.

AU - Wegman-Ostrosky, T.

AU - Frone, M.N.

AU - Johnston, J.J.

AU - Nickerson, M.L.

AU - Rotunno, M.

AU - Li, S.A.

AU - Achatz, M.I.

AU - Brodie, S.A.

AU - Dean, M.

AU - De Andrade, K.C.

AU - Fortes, F.P.

AU - Gianferante, M.

AU - Khincha, P.

AU - McMaster, M.L.

AU - McReynolds, L.J.

AU - Pemov, A.

AU - Pinheiro, M.

AU - Santiago, K.M.

AU - Alter, B.P.

AU - Caporaso, N.E.

AU - Gadalla, S.M.

AU - Goldin, L.R.

AU - Greene, M.H.

AU - Loud, J.

AU - Yang, X.R.

AU - Freedman, N.D.

AU - Gapstur, S.M.

AU - Gaudet, M.M.

AU - Calista, D.

AU - Ghiorzo, P.

AU - Fargnoli, M.C.

AU - Nagore, E.

AU - Peris, K.

AU - Puig, S.

AU - Landi, M.T.

AU - Hicks, B.

AU - Zhu, B.

AU - Liu, J.

AU - Sampson, J.N.

AU - Chanock, S.J.

AU - Mirabello, L.J.

AU - Morton, L.M.

AU - Biesecker, L.G.

AU - Tucker, M.A.

AU - Savage, S.A.

AU - Goldstein, A.M.

AU - Stewart, D.R.

N1 - cited By 0

PY - 2018

Y1 - 2018

N2 - 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).

AB - 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).

U2 - 10.1186/s13073-018-0607-5

DO - 10.1186/s13073-018-0607-5

M3 - Article

VL - 10

JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

IS - 1

ER -