ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9578C>T (p.Thr3193Ile)

dbSNP: rs2073041128
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001182878 SCV001348477 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-24 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 3193 of the BRCA2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant 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). 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.
Ambry Genetics RCV001182878 SCV002694707 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-17 criteria provided, single submitter clinical testing The p.T3193I variant (also known as c.9578C>T), located in coding exon 25 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9578. The threonine at codon 3193 is replaced by isoleucine, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV003645202 SCV004377707 uncertain significance Hereditary breast ovarian cancer syndrome 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3193 of the BRCA2 protein (p.Thr3193Ile). 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: 922690). 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.

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