Submissions for variant NM_000059.4(BRCA2):c.8040C>G (p.Asp2680Glu)

dbSNP: rs876660013

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218538	SCV000277066	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	The p.D2680E variant (also known as c.8040C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8040. The aspartic acid at codon 2680 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was also detected on a 25-gene panel test in a woman of mixed ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration was observed in with an allele frequency of 0.00028 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00098 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0010 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083).This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535538	SCV000635630	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 2680 of the BRCA2 protein (p.Asp2680Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 232824). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000218538	SCV000904795	likely benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001753675	SCV002005453	uncertain significance	not provided	2019-12-23	criteria provided, single submitter	clinical testing	Observed in breast cancer cases and controls in a Japanese case-control study (Momozawa 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 8268C>G; This variant is associated with the following publications: (PMID: 30287823)
Baylor Genetics	RCV004567618	SCV005059165	uncertain significance	Familial cancer of breast	2023-12-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001753675	SCV005625308	uncertain significance	not provided	2024-11-08	criteria provided, single submitter	clinical testing	The BRCA2 c.8040C>G (p.Asp2680Glu) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 25186627 (2015), 30287823 (2018)) as well as reportedly healthy individuals (PMID: 30287823 (2018), 36243179 (2022)). This variant was also reported to be functionally neutral in a homologous recombination assay (PMID: 37731132 (2023)). The frequency of this variant in the general population, 0.0000066 (1/152100 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.