Submissions for variant NM_000059.4(BRCA2):c.7828G>A (p.Val2610Met)

dbSNP: rs587780661

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122932	SCV000166190	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2610 of the BRCA2 protein (p.Val2610Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24489791, 25186627, 31090900). ClinVar contains an entry for this variant (Variation ID: 135816). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000217800	SCV000276951	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.V2610M variant (also known as c.7828G>A), located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7828. The valine at codon 2610 is replaced by methionine, an amino acid with highly similar properties. One study performed a RT-PCR splicing assay which found no evidence of aberrant transcripts due to the p.V2610M variant (Whiley PJ et al. PLoS ONE 2014; 9(1):e86836). This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000589148	SCV000568487	uncertain significance	not provided	2022-06-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8056G>A; Observed in individuals with a personal and/or family history of breast cancer (Whiley 2014, Tung 2015); This variant is associated with the following publications: (PMID: 26913838, 26207792, 24489791, 12228710, 27433848, 31131967, 20858050, 25186627, 31090900)
Color Diagnostics, LLC DBA Color Health	RCV000217800	SCV000689071	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 2610 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast cancer (PMID: 25186627, 31090900). This variant was reported in a multifactorial analysis with a segregation, co-occurrence, and family history likelihood ratios for pathogenicity of 0.83, 1.024, and 4.446, respectively (PMID: 31131967). This variant has not been identified 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	RCV000855636	SCV000695104	uncertain significance	not specified	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7828G>A (p.Val2610Met) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7828G>A has been reported in the literature in individuals affected with breast cancer (Tung_2015, Nones_2019). However these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Whiley et al reported that even though bioinformatic predication suggested that this variant may affect mRNA splicing, splicing assays further showed no impact on mRNA splicing (Whiley_2014). The following publications have been ascertained in the context of this evaluation (PMID: 20858050, 26207792, 31090900, 25186627, 24489791). ClinVar contains an entry for this variant (Variation ID: 135816). Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center	RCV003607241	SCV004543918	uncertain significance	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: PP3, PS1_MOD, PM2_SUP, BS7_SUP(RNA)
All of Us Research Program, National Institutes of Health	RCV003997394	SCV004845563	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589148	SCV005625296	uncertain significance	not provided	2024-02-29	criteria provided, single submitter	clinical testing	The BRCA2 c.7828G>A (p.Val2610Met) variant has been reported in the published literature in affected individuals with breast cancer (PMIDs: 24489791 (2014), 25186627 (2015), and 31090900 (2019)). A splicing assay found that this variant was not damaging to protein function (PMID: 24489791 (2014)). In addition, a multifactorial likelihood analysis classified this variant as a variant of uncertain significance (PMID: 31131967 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.