Submissions for variant NM_000059.4(BRCA2):c.9911G>A (p.Cys3304Tyr)

dbSNP: rs876658506

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223068	SCV000273838	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The p.C3304Y variant (also known as c.9911G>A), located in coding exon 26 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9911. The cysteine at codon 3304 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is 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	RCV000551258	SCV000635767	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-30	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 3304 of the BRCA2 protein (p.Cys3304Tyr). 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: 230326). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV004783765	SCV005396400	uncertain significance	not provided	2024-05-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 10139G>A
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004783765	SCV005625363	uncertain significance	not provided	2024-07-03	criteria provided, single submitter	clinical testing	The BRCA2 c.9911G>A (p.Cys3304Tyr) variant has not been reported as a germline variant in individuals with BRCA2-related conditions in the published literature. However, it has been described as functionally neutral based on a computational analysis (PMID: 29884841 (2019)). The frequency of this variant in the general population, 0.00071 (13/18346 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055757	SCV005726716	uncertain significance	not specified	2024-11-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9911G>A (p.Cys3304Tyr) results in a non-conservative amino acid change located in the BRCA2 TR2 domain (IPR055077) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251252 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.9911G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 230326). Based on the evidence outlined above, the variant was classified as uncertain significance.