ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4208C>T (p.Thr1403Ile)

dbSNP: rs2072498862
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001298801 SCV001487868 uncertain significance Hereditary breast ovarian cancer syndrome 2020-08-08 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 1403 of the BRCA2 protein (p.Thr1403Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant has not been reported in the literature in individuals with BRCA2-related conditions. 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.
Ambry Genetics RCV002327642 SCV002630683 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-20 criteria provided, single submitter clinical testing The p.T1403I variant (also known as c.4208C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 4208. The threonine at codon 1403 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV002327642 SCV003848766 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
GeneDx RCV004779042 SCV005392419 uncertain significance not provided 2024-04-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 4436C>T

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