Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay
Abstract Next-generation sequencing of Sri Lankan families with inherited cancer syndromes resulted in the identification of five BRCA2 variants of unknown clinical significance. Interpreting such variants poses significant challenges for both clinicians and patients. Using a mouse embryonic stem ce...
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doaj-cc565824eef444bba709fc44ba390f052021-04-02T13:21:24ZengBMCBreast Cancer Research1465-542X2020-05-012211510.1186/s13058-020-01272-zFunctional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assayNirmala Sirisena0Kajal Biswas1Teresa Sullivan2Stacey Stauffer3Linda Cleveland4Eileen Southon5Vajira H. W. Dissanayake6Shyam K. Sharan7Human Genetics Unit, Faculty of Medicine, University of ColomboMouse Cancer Genetics Program, Center for Cancer Research, National Cancer InstituteMouse Cancer Genetics Program, Center for Cancer Research, National Cancer InstituteMouse Cancer Genetics Program, Center for Cancer Research, National Cancer InstituteMouse Cancer Genetics Program, Center for Cancer Research, National Cancer InstituteMouse Cancer Genetics Program, Center for Cancer Research, National Cancer InstituteHuman Genetics Unit, Faculty of Medicine, University of ColomboMouse Cancer Genetics Program, Center for Cancer Research, National Cancer InstituteAbstract Next-generation sequencing of Sri Lankan families with inherited cancer syndromes resulted in the identification of five BRCA2 variants of unknown clinical significance. Interpreting such variants poses significant challenges for both clinicians and patients. Using a mouse embryonic stem cell-based functional assay, we found I785V, N830D, and K2077N to be functionally indistinguishable from wild-type BRCA2. Specific but mild sensitivity to olaparib and reduction in homologous recombination (HR) efficiency suggest partial loss of function of the A262T variant. This variant is located in the N-terminal DNA binding domain of BRCA2 that can facilitate HR by binding to dsDNA/ssDNA junctions. P3039P is clearly pathogenic because of premature protein truncation caused by exon 23 skipping. These findings highlight the value of mouse embryonic stem cell-based assays for determining the functional significance of variants of unknown clinical significance and provide valuable information regarding risk estimation and genetic counseling of families carrying these BRCA2 variants.http://link.springer.com/article/10.1186/s13058-020-01272-zBRCA2ClassificationFunctional assayInherited cancerNext-generation sequencingVariants of unknown clinical significance (VUS) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nirmala Sirisena Kajal Biswas Teresa Sullivan Stacey Stauffer Linda Cleveland Eileen Southon Vajira H. W. Dissanayake Shyam K. Sharan |
spellingShingle |
Nirmala Sirisena Kajal Biswas Teresa Sullivan Stacey Stauffer Linda Cleveland Eileen Southon Vajira H. W. Dissanayake Shyam K. Sharan Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay Breast Cancer Research BRCA2 Classification Functional assay Inherited cancer Next-generation sequencing Variants of unknown clinical significance (VUS) |
author_facet |
Nirmala Sirisena Kajal Biswas Teresa Sullivan Stacey Stauffer Linda Cleveland Eileen Southon Vajira H. W. Dissanayake Shyam K. Sharan |
author_sort |
Nirmala Sirisena |
title |
Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay |
title_short |
Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay |
title_full |
Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay |
title_fullStr |
Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay |
title_full_unstemmed |
Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay |
title_sort |
functional evaluation of five brca2 unclassified variants identified in a sri lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2020-05-01 |
description |
Abstract Next-generation sequencing of Sri Lankan families with inherited cancer syndromes resulted in the identification of five BRCA2 variants of unknown clinical significance. Interpreting such variants poses significant challenges for both clinicians and patients. Using a mouse embryonic stem cell-based functional assay, we found I785V, N830D, and K2077N to be functionally indistinguishable from wild-type BRCA2. Specific but mild sensitivity to olaparib and reduction in homologous recombination (HR) efficiency suggest partial loss of function of the A262T variant. This variant is located in the N-terminal DNA binding domain of BRCA2 that can facilitate HR by binding to dsDNA/ssDNA junctions. P3039P is clearly pathogenic because of premature protein truncation caused by exon 23 skipping. These findings highlight the value of mouse embryonic stem cell-based assays for determining the functional significance of variants of unknown clinical significance and provide valuable information regarding risk estimation and genetic counseling of families carrying these BRCA2 variants. |
topic |
BRCA2 Classification Functional assay Inherited cancer Next-generation sequencing Variants of unknown clinical significance (VUS) |
url |
http://link.springer.com/article/10.1186/s13058-020-01272-z |
work_keys_str_mv |
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