ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.1253A>G (p.Tyr418Cys)

gnomAD frequency: 0.00001  dbSNP: rs773947541
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000690110 SCV000817788 uncertain significance BAP1-related tumor predisposition syndrome 2023-12-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 418 of the BAP1 protein (p.Tyr418Cys). This variant is present in population databases (rs773947541, gnomAD 0.006%). This missense change has been observed in individual(s) with melanoma (PMID: 28062663). ClinVar contains an entry for this variant (Variation ID: 569477). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 RCV000771526 SCV000904062 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-05 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 418 of the BAP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that this variant has no significant impact in deubiquitinase assays (PMID: 28062663). This variant has been reported in individuals affected with melanoma (PMID: 28062663). This variant has been identified in 3/251194 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 RCV000771526 SCV001170770 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-01 criteria provided, single submitter clinical testing The p.Y418C variant (also known as c.1253A>G), located in coding exon 13 of the BAP1 gene, results from an A to G substitution at nucleotide position 1253. The tyrosine at codon 418 is replaced by cysteine, an amino acid with highly dissimilar properties. One study identified this alteration in 1/1977 melanoma patients and 0/754 controls (O'Shea SJ et al. Hum. Mol. Genet., 2017 02;26:717-728). This amino acid position is 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 RCV003163142 SCV003915110 uncertain significance not provided 2023-04-07 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with melanoma (O'Shea et al., 2017); This variant is associated with the following publications: (PMID: 28062663)

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