Submissions for variant NM_000059.4(BRCA2):c.8494G>C (p.Glu2832Gln)

dbSNP: rs876658951

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214685	SCV000274832	uncertain significance	Hereditary cancer-predisposing syndrome	2015-03-28	criteria provided, single submitter	clinical testing	The p.E2832Q variant (also known as c.8494G>C and 8722G>C), located in coding exon 19 of the BRCA2 gene, results from a G to C substitution at nucleotide position 8494. The glutamic acid at codon 2832 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. 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 p.E2832Q remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000214685	SCV001345182	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 2832 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853538	SCV002314127	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-07-26	criteria provided, single submitter	clinical testing	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. This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 2832 of the BRCA2 protein (p.Glu2832Gln). 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: 231088). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358025	SCV001553657	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu2832Gln variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB database. The variant was identified in dbSNP (rs876658951) as “with pathogenic, uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Glu2832 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.