Submissions for variant NM_004656.4(BAP1):c.1912T>C (p.Cys638Arg)

dbSNP: rs1578219121

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795973	SCV000935455	uncertain significance	BAP1-related tumor predisposition syndrome	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 638 of the BAP1 protein (p.Cys638Arg). This variant is not present in population databases (gnomAD no frequency). 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: 642497). 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.
Color Diagnostics, LLC DBA Color Health	RCV001188269	SCV001355290	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-18	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 638 of the BAP1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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	RCV001188269	SCV002723301	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-09	criteria provided, single submitter	clinical testing	The p.C638R variant (also known as c.1912T>C), located in coding exon 15 of the BAP1 gene, results from a T to C substitution at nucleotide position 1912. The cysteine at codon 638 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.