Submissions for variant NM_000059.4(BRCA2):c.6413T>A (p.Val2138Asp)

gnomAD frequency: 0.00001  dbSNP: rs80358877

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223184	SCV000278773	likely benign	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000767077	SCV000565988	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015); Also known as 6641T>A; This variant is associated with the following publications: (PMID: 31131967, 24728327, 25980754)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767077	SCV000600700	uncertain significance	not provided	2022-12-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00017 (5/30274 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals suspected of Lynch Syndrome (PMID: 25980754 (2015)) as well as in healthy controls (PMID: 24728327 (2014)). A published study using BRCA2-deficient cells and poly (ADP-ribose) polymerase (PARP) inhibitors suggested that this variant has no damaging effect on protein function, but further studies are required to confirm the functional efficiency of this variant (PMID: 32444794 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000223184	SCV000911868	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces valine with aspartic acid at codon 2138 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function, as assayed by response to PARP inhibitors (PMID: 32444794). This variant has been reported in an individual suspected to be affected with Lynch syndrome and an individual affected with breast cancer (PMID: 25980754, DOI: 10.1158/1538-7445.SABCS21-P3-07-07). The individual affected with breast cancer also carried a pathogenic variant in the BRCA1 gene that could explain the observed phenotype (DOI: 10.1158/1538-7445.SABCS21-P3-07-07). This variant has been identified in 5/234562 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120349	SCV001467841	uncertain significance	not specified	2024-06-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6413T>A (p.Val2138Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 242246 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6413T>A has been reported in the literature as a VUS in a study reporting multigene panel findings among individuals who underwent clinical genetic testing for Lynch syndrome (example, Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a high-throughput functional evaluation utilizing BRCA2-deficient cells and poly (ADP-ribose) polymerase (PARP) inhibitors (Ikegami_2020). The following publications have been ascertained in the context of this evaluation (PMID: 30630528, 32444794, 25980754). ClinVar contains an entry for this variant (Variation ID: 52088). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001421968	SCV001624502	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-26	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000223184	SCV003852504	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000113585	SCV004844259	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces valine with aspartic acid at codon 2138 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function, as assayed by response to PARP inhibitors (PMID: 32444794). This variant has been reported in an individual suspected to be affected with Lynch syndrome and an individual affected with breast cancer (PMID: 25980754, DOI: 10.1158/1538-7445.SABCS21-P3-07-07). The individual affected with breast cancer also carried a pathogenic variant in the BRCA1 gene that could explain the observed phenotype (DOI: 10.1158/1538-7445.SABCS21-P3-07-07). This variant has been identified in 5/234562 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ITMI	RCV000120349	SCV000084501	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113585	SCV000146847	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000120349	SCV000587844	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research