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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
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 c...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305568/ https://www.ncbi.nlm.nih.gov/pubmed/30583724 http://dx.doi.org/10.1186/s13073-018-0607-5 |
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author | Kim, Jung Luo, Wen Wang, Mingyi Wegman-Ostrosky, Talia Frone, Megan N. Johnston, Jennifer J. Nickerson, Michael L. Rotunno, Melissa Li, Shengchao A. Achatz, Maria I. Brodie, Seth A. 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. |
author_facet | Kim, Jung Luo, Wen Wang, Mingyi Wegman-Ostrosky, Talia Frone, Megan N. Johnston, Jennifer J. Nickerson, Michael L. Rotunno, Melissa Li, Shengchao A. Achatz, Maria I. Brodie, Seth A. 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. |
author_sort | Kim, Jung |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13073-018-0607-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6305568 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-63055682019-01-02 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, Jung Luo, Wen Wang, Mingyi Wegman-Ostrosky, Talia Frone, Megan N. Johnston, Jennifer J. Nickerson, Michael L. Rotunno, Melissa Li, Shengchao A. Achatz, Maria I. Brodie, Seth A. 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. Genome Med Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13073-018-0607-5) contains supplementary material, which is available to authorized users. BioMed Central 2018-12-24 /pmc/articles/PMC6305568/ /pubmed/30583724 http://dx.doi.org/10.1186/s13073-018-0607-5 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Kim, Jung Luo, Wen Wang, Mingyi Wegman-Ostrosky, Talia Frone, Megan N. Johnston, Jennifer J. Nickerson, Michael L. Rotunno, Melissa Li, Shengchao A. Achatz, Maria I. Brodie, Seth A. 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. 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 |
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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305568/ https://www.ncbi.nlm.nih.gov/pubmed/30583724 http://dx.doi.org/10.1186/s13073-018-0607-5 |
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