Submissions for variant NM_000059.4(BRCA2):c.9794G>A (p.Cys3265Tyr)

dbSNP: rs899192725

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001019759	SCV001181158	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	The p.C3265Y variant (also known as c.9794G>A), located in coding exon 26 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9794. The cysteine at codon 3265 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was identified in an Argentinian individual with personal history of breast cancer at ages 50 and 52 (Solano AR et al. Oncotarget, 2017 Sep;8:60487-60495). 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.
Color Diagnostics, LLC DBA Color Health	RCV001019759	SCV001359227	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-11	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 3265 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 been reported in an individual affected with breast cancer (PMID: 27463008). 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	RCV001873322	SCV002239394	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 3265 of the BRCA2 protein (p.Cys3265Tyr). 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: 823482). 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.