ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4036A>G (p.Thr1346Ala)

dbSNP: rs2137502300
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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 RCV001981453 SCV002222353 uncertain significance Hereditary breast ovarian cancer syndrome 2024-10-06 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1346 of the BRCA2 protein (p.Thr1346Ala). 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: 1443847). 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.
Ambry Genetics RCV002352627 SCV002623423 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-28 criteria provided, single submitter clinical testing The p.T1346A variant (also known as c.4036A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4036. The threonine at codon 1346 is replaced by alanine, 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.
GeneDx RCV003149011 SCV003837545 uncertain significance not provided 2023-05-28 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 4264A>G; This variant is associated with the following publications: (PMID: 31911673)
University of Washington Department of Laboratory Medicine, University of Washington RCV002352627 SCV003848626 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).

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