ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.1748C>T (p.Ser583Leu)

gnomAD frequency: 0.00001  dbSNP: rs369259771
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475113 SCV000553955 uncertain significance BAP1-related tumor predisposition syndrome 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 583 of the BAP1 protein (p.Ser583Leu). This variant is present in population databases (rs369259771, gnomAD 0.0009%). This missense change has been observed in individual(s) with malignant mesothelioma and basal cell carcinoma (PMID: 26719535). ClinVar contains an entry for this variant (Variation ID: 412429). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BAP1 function (PMID: 26719535). 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 RCV000581046 SCV000682593 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-26 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 583 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). A functional study has shown that this variant causes a mild decrease in BAP1 enzymatic activity (PMID: 26719535). This variant has been reported as a germline variant in an asbestos-exposed individual affected with mesothelioma and basal cell carcinoma. The proband's child of unknown genotype died of cutaneous melanoma (PMID: 26719535). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/246024 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.
GeneDx RCV001552368 SCV001773041 uncertain significance not provided 2022-12-07 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; Published functional studies are inconclusive: associated with normal ASXL2 binding and moderately decreased enzyme activity compared to wild type (Ohar et al., 2016); Observed in an individual with mesothelioma and basal cell carcinoma (Ohar et al., 2016); This variant is associated with the following publications: (PMID: 27181379, 26719535)
Mendelics RCV002248694 SCV002517916 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000581046 SCV002711613 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-03 criteria provided, single submitter clinical testing The p.S583L variant (also known as c.1748C>T), located in coding exon 14 of the BAP1 gene, results from a C to T substitution at nucleotide position 1748. The serine at codon 583 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with malignant mesothelioma (Ohar JA et al. Cancer Res., 2016 Jan;76:206-15).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.

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