ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.1837A>G (p.Thr613Ala)

gnomAD frequency: 0.00001  dbSNP: rs749728488
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000536396 SCV000651868 uncertain significance BAP1-related tumor predisposition syndrome 2024-08-19 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 613 of the BAP1 protein (p.Thr613Ala). This variant is present in population databases (rs749728488, gnomAD 0.002%). This missense change has been observed in individual(s) with melanoma (PMID: 28062663). ClinVar contains an entry for this variant (Variation ID: 472681). 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 BAP1 protein function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health RCV000774725 SCV000908667 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-22 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 613 of the BAP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with melanoma in the literature (PMID 28062663). This variant has been identified in 2/251426 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.
Ambry Genetics RCV000774725 SCV001173878 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-13 criteria provided, single submitter clinical testing The p.T613A variant (also known as c.1837A>G), located in coding exon 14 of the BAP1 gene, results from an A to G substitution at nucleotide position 1837. The threonine at codon 613 is replaced by alanine, an amino acid with similar properties. In one study, this variant was seen in 1/1977 melanoma cases and 0/754 controls (O'Shea SJ et al. Hum. Mol. Genet. 2017 02;26:717-728). 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.

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