Submissions for variant NM_000059.4(BRCA2):c.3004A>G (p.Asn1002Asp)

gnomAD frequency: 0.00001  dbSNP: rs780365246

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001343189	SCV001537153	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-07-12	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1039670). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1002 of the BRCA2 protein (p.Asn1002Asp). This variant is present in population databases (rs780365246, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 20858050). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003158779	SCV003850306	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).
Ambry Genetics	RCV003158779	SCV005552949	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-05	criteria provided, single submitter	clinical testing	The p.N1002D variant (also known as c.3004A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3004. The asparagine at codon 1002 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998838	SCV005624380	uncertain significance	not provided	2024-03-20	criteria provided, single submitter	clinical testing	The BRCA2 c.3004A>G (p.Asn1002Asp) variant has not been reported in individuals with BRCA2-related conditions in the published literature. The frequency of this variant in the general population, 0.000099 (1/10064 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.