ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9758G>A (p.Cys3253Tyr)

gnomAD frequency: 0.00001  dbSNP: rs786202698
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165636 SCV000216372 uncertain significance Hereditary cancer-predisposing syndrome 2024-09-29 criteria provided, single submitter clinical testing The p.C3253Y variant (also known as c.9758G>A), located in coding exon 26 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9758. The cysteine at codon 3253 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was reported in a case-control study in an Indian woman with a family history of early-onset breast cancer (Juwle A et al. Med. Oncol., 2012 Dec;29:3272-81). 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.
Color Diagnostics, LLC DBA Color Health RCV000165636 SCV000906824 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-06 criteria provided, single submitter clinical testing This missense variant replaces cysteine with tyrosine at codon 3253 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 22752604). This variant has been identified in 2/251390 chromosomes 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 RCV002515153 SCV003462091 uncertain significance Hereditary breast ovarian cancer syndrome 2024-11-05 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 3253 of the BRCA2 protein (p.Cys3253Tyr). This variant is present in population databases (rs786202698, gnomAD 0.003%). This missense change has been observed in individual(s) with a family history of breast cancer (PMID: 22752604, 35534704). This variant is also known as 9986G>A. ClinVar contains an entry for this variant (Variation ID: 186106). 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.

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