ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.1943C>T (p.Ala648Val)

gnomAD frequency: 0.00001  dbSNP: rs755915077
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567366 SCV000672787 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-27 criteria provided, single submitter clinical testing The p.A648V variant (also known as c.1943C>T), located in coding exon 15 of the BAP1 gene, results from a C to T substitution at nucleotide position 1943. The alanine at codon 648 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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.
Color Diagnostics, LLC DBA Color Health RCV000567366 SCV000687978 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing
Invitae RCV000816277 SCV000956778 uncertain significance BAP1-related tumor predisposition syndrome 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 648 of the BAP1 protein (p.Ala648Val). This variant is present in population databases (rs755915077, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 485265). 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 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.
GeneDx RCV003236817 SCV003935716 uncertain significance not provided 2023-06-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with renal papillary cell carcinoma (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29684080, 24686850)

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