Submissions for variant NM_000059.4(BRCA2):c.2922C>G (p.Asp974Glu)

dbSNP: rs929538989

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000560988	SCV000661237	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-08	criteria provided, single submitter	clinical testing	The p.D974E variant (also known as c.2922C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 2922. The aspartic acid at codon 974 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779991	SCV000916976	uncertain significance	not specified	2024-10-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2922C>G (p.Asp974Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249060 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2922C>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 479294). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001038891	SCV001202391	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-09	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 974 of the BRCA2 protein (p.Asp974Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 479294). 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	RCV000560988	SCV001357876	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 974 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the Leiden Open-source Variation Database (https://databases.lovd.nl/shared/individuals/00174456). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000560988	SCV003850239	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478203	SCV004219560	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004802189	SCV005424353	uncertain significance	BRCA2-related cancer predisposition	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 974 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the Leiden Open-source Variation Database (https://databases.lovd.nl/shared/individuals/00174456). 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.