Submissions for variant NM_000059.4(BRCA2):c.8296A>G (p.Thr2766Ala)

dbSNP: rs774027004

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001801048	SCV002046436	uncertain significance	not provided	2024-05-10	criteria provided, single submitter	clinical testing	The BRCA2 c.8296A>G (p.Thr2766Ala) variant has been reported in the published literature in an individual with breast and/or ovarian cancer (PMID: 29215753 (2018)). The frequency of this variant in the general population, 0.000008 (2/248554 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001885241	SCV002191419	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-13	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. 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. ClinVar contains an entry for this variant (Variation ID: 1330031). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29215753). This variant is present in population databases (rs774027004, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2766 of the BRCA2 protein (p.Thr2766Ala).
Sema4, Sema4	RCV002256841	SCV002531928	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
Ambry Genetics	RCV002256841	SCV002679265	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	clinical testing	The p.T2766A variant (also known as c.8296A>G), located in coding exon 17 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8296. The threonine at codon 2766 is replaced by alanine, an amino acid with 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.
GeneDx	RCV001801048	SCV005385834	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast and/or ovarian cancer (PMID: 29215753); This variant is associated with the following publications: (PMID: 12228710, 29884841, 32377563, 29215753)