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The functional impact of variants of uncertain significance in BRCA2

PURPOSE: Genetic testing has uncovered large numbers of variants in the BRCA2 gene for which the clinical significance is unclear. Cancer risk prediction of these variants of uncertain significance (VUS) can be improved by reliable assessment of the extent of impairment of the tumor suppressor funct...

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Autores principales: Mesman, Romy L. S., Calléja, Fabienne M. G. R., Hendriks, Giel, Morolli, Bruno, Misovic, Branislav, Devilee, Peter, van Asperen, Christi J., Vrieling, Harry, Vreeswijk, Maaike P. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752316/
https://www.ncbi.nlm.nih.gov/pubmed/29988080
http://dx.doi.org/10.1038/s41436-018-0052-2
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author Mesman, Romy L. S.
Calléja, Fabienne M. G. R.
Hendriks, Giel
Morolli, Bruno
Misovic, Branislav
Devilee, Peter
van Asperen, Christi J.
Vrieling, Harry
Vreeswijk, Maaike P. G.
author_facet Mesman, Romy L. S.
Calléja, Fabienne M. G. R.
Hendriks, Giel
Morolli, Bruno
Misovic, Branislav
Devilee, Peter
van Asperen, Christi J.
Vrieling, Harry
Vreeswijk, Maaike P. G.
author_sort Mesman, Romy L. S.
collection PubMed
description PURPOSE: Genetic testing has uncovered large numbers of variants in the BRCA2 gene for which the clinical significance is unclear. Cancer risk prediction of these variants of uncertain significance (VUS) can be improved by reliable assessment of the extent of impairment of the tumor suppressor function(s) of BRCA2. METHODS: Here, we evaluated the performance of the mouse embryonic stem cell (mESC)-based functional assay on an extensive set of BRCA2 missense variants. RESULTS: Whereas all 20 nonpathogenic (class 1/2) variants were able to complement the cell lethal phenotype induced by loss of endogenous mouse Brca2, only 1 out of 15 pathogenic (class 4/5) variants (p.Gly2609Asp) was able to do so. However, in this variant the major tumor suppressive activity of BRCA2, i.e., homology directed repair (HDR), was severely abrogated. Among 43 evaluated VUS (class 3), 7 were unable to complement the lethal phenotype of mouse Brca2 loss while 7 other variants displayed a more severe reduction of HDR activity than observed for class 1/ 2 variants. CONCLUSION: The mESC-based BRCA2 functional assay can reliably determine the functional impact of VUS, distinguish between pathogenic and nonpathogenic variants, and may contribute to improved cancer risk estimation for BRCA2 VUS carriers.
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spelling pubmed-67523162019-09-23 The functional impact of variants of uncertain significance in BRCA2 Mesman, Romy L. S. Calléja, Fabienne M. G. R. Hendriks, Giel Morolli, Bruno Misovic, Branislav Devilee, Peter van Asperen, Christi J. Vrieling, Harry Vreeswijk, Maaike P. G. Genet Med Article PURPOSE: Genetic testing has uncovered large numbers of variants in the BRCA2 gene for which the clinical significance is unclear. Cancer risk prediction of these variants of uncertain significance (VUS) can be improved by reliable assessment of the extent of impairment of the tumor suppressor function(s) of BRCA2. METHODS: Here, we evaluated the performance of the mouse embryonic stem cell (mESC)-based functional assay on an extensive set of BRCA2 missense variants. RESULTS: Whereas all 20 nonpathogenic (class 1/2) variants were able to complement the cell lethal phenotype induced by loss of endogenous mouse Brca2, only 1 out of 15 pathogenic (class 4/5) variants (p.Gly2609Asp) was able to do so. However, in this variant the major tumor suppressive activity of BRCA2, i.e., homology directed repair (HDR), was severely abrogated. Among 43 evaluated VUS (class 3), 7 were unable to complement the lethal phenotype of mouse Brca2 loss while 7 other variants displayed a more severe reduction of HDR activity than observed for class 1/ 2 variants. CONCLUSION: The mESC-based BRCA2 functional assay can reliably determine the functional impact of VUS, distinguish between pathogenic and nonpathogenic variants, and may contribute to improved cancer risk estimation for BRCA2 VUS carriers. Nature Publishing Group US 2018-07-10 2019 /pmc/articles/PMC6752316/ /pubmed/29988080 http://dx.doi.org/10.1038/s41436-018-0052-2 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
spellingShingle Article
Mesman, Romy L. S.
Calléja, Fabienne M. G. R.
Hendriks, Giel
Morolli, Bruno
Misovic, Branislav
Devilee, Peter
van Asperen, Christi J.
Vrieling, Harry
Vreeswijk, Maaike P. G.
The functional impact of variants of uncertain significance in BRCA2
title The functional impact of variants of uncertain significance in BRCA2
title_full The functional impact of variants of uncertain significance in BRCA2
title_fullStr The functional impact of variants of uncertain significance in BRCA2
title_full_unstemmed The functional impact of variants of uncertain significance in BRCA2
title_short The functional impact of variants of uncertain significance in BRCA2
title_sort functional impact of variants of uncertain significance in brca2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752316/
https://www.ncbi.nlm.nih.gov/pubmed/29988080
http://dx.doi.org/10.1038/s41436-018-0052-2
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