Submissions for variant NM_000059.4(BRCA2):c.8440A>G (p.Asn2814Asp)

gnomAD frequency: 0.00001  dbSNP: rs876660312

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213395	SCV000277637	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-15	criteria provided, single submitter	clinical testing	The p.N2814D variant (also known as c.8440A>G), located in coding exon 18 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8440. The asparagine at codon 2814 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054105	SCV001218401	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2814 of the BRCA2 protein (p.Asn2814Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 233292). 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	RCV000213395	SCV001352374	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 2814 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 colorectal cancer (PMID: 33359728). 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	RCV001280582	SCV001467789	uncertain significance	not specified	2020-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8440A>G (p.Asn2814Asp) results in a 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 was absent in 251384 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.8440A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001770183	SCV002004387	uncertain significance	not provided	2020-04-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
All of Us Research Program, National Institutes of Health	RCV004804922	SCV004846021	uncertain significance	BRCA2-related cancer predisposition	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 2814 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001770183	SCV005625320	uncertain significance	not provided	2024-05-10	criteria provided, single submitter	clinical testing	The BRCA2 c.8440A>G (p.Asn2814Asp) variant has been reported in the published literature in an individual with colorectal cancer (PMID: 33359728 (2022)). The frequency of this variant in the general population, 0.0000066 (1/152138 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004725090	SCV005336667	uncertain significance	BRCA2-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The BRCA2 c.8440A>G variant is predicted to result in the amino acid substitution p.Asn2814Asp. This variant has been reported in an individual with young onset colorectal cancer (Supplementary Table 1, Dharwadkar et al. 2020. PubMed ID: 33359728). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/233292/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.