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Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases
Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate varia...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567983/ https://www.ncbi.nlm.nih.gov/pubmed/25782689 http://dx.doi.org/10.1007/s12687-015-0220-x |
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author | Vail, Paris J. Morris, Brian van Kan, Aric Burdett, Brianna C. Moyes, Kelsey Theisen, Aaron Kerr, Iain D. Wenstrup, Richard J. Eggington, Julie M. |
author_facet | Vail, Paris J. Morris, Brian van Kan, Aric Burdett, Brianna C. Moyes, Kelsey Theisen, Aaron Kerr, Iain D. Wenstrup, Richard J. Eggington, Julie M. |
author_sort | Vail, Paris J. |
collection | PubMed |
description | Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate variant interpretation via aggregated data. If LSDBs are to be used for clinical practice, consistent and transparent criteria regarding the deposition and interpretation of variants are vital, as variant classifications are often used to make important and irreversible clinical decisions. In this study, we performed a retrospective analysis of 2017 consecutive BRCA1 and BRCA2 genetic variants identified from 24,650 consecutive patient samples referred to our laboratory to establish an unbiased dataset representative of the types of variants seen in the US patient population, submitted by clinicians and researchers for BRCA1 and BRCA2 testing. We compared the clinical classifications of these variants among five publicly accessible BRCA1 and BRCA2 variant databases: BIC, ClinVar, HGMD (paid version), LOVD, and the UMD databases. Our results show substantial disparity of variant classifications among publicly accessible databases. Furthermore, it appears that discrepant classifications are not the result of a single outlier but widespread disagreement among databases. This study also shows that databases sometimes favor a clinical classification when current best practice guidelines (ACMG/AMP/CAP) would suggest an uncertain classification. Although LSDBs have been well established for research applications, our results suggest several challenges preclude their wider use in clinical practice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12687-015-0220-x) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4567983 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-45679832015-09-15 Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases Vail, Paris J. Morris, Brian van Kan, Aric Burdett, Brianna C. Moyes, Kelsey Theisen, Aaron Kerr, Iain D. Wenstrup, Richard J. Eggington, Julie M. J Community Genet Original Article Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate variant interpretation via aggregated data. If LSDBs are to be used for clinical practice, consistent and transparent criteria regarding the deposition and interpretation of variants are vital, as variant classifications are often used to make important and irreversible clinical decisions. In this study, we performed a retrospective analysis of 2017 consecutive BRCA1 and BRCA2 genetic variants identified from 24,650 consecutive patient samples referred to our laboratory to establish an unbiased dataset representative of the types of variants seen in the US patient population, submitted by clinicians and researchers for BRCA1 and BRCA2 testing. We compared the clinical classifications of these variants among five publicly accessible BRCA1 and BRCA2 variant databases: BIC, ClinVar, HGMD (paid version), LOVD, and the UMD databases. Our results show substantial disparity of variant classifications among publicly accessible databases. Furthermore, it appears that discrepant classifications are not the result of a single outlier but widespread disagreement among databases. This study also shows that databases sometimes favor a clinical classification when current best practice guidelines (ACMG/AMP/CAP) would suggest an uncertain classification. Although LSDBs have been well established for research applications, our results suggest several challenges preclude their wider use in clinical practice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12687-015-0220-x) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2015-03-18 2015-10 /pmc/articles/PMC4567983/ /pubmed/25782689 http://dx.doi.org/10.1007/s12687-015-0220-x Text en © The Author(s) 2015 https://creativecommons.org/licenses/by/4.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Article Vail, Paris J. Morris, Brian van Kan, Aric Burdett, Brianna C. Moyes, Kelsey Theisen, Aaron Kerr, Iain D. Wenstrup, Richard J. Eggington, Julie M. Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases |
title | Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases |
title_full | Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases |
title_fullStr | Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases |
title_full_unstemmed | Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases |
title_short | Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases |
title_sort | comparison of locus-specific databases for brca1 and brca2 variants reveals disparity in variant classification within and among databases |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567983/ https://www.ncbi.nlm.nih.gov/pubmed/25782689 http://dx.doi.org/10.1007/s12687-015-0220-x |
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