Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000561640 | SCV000664605 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-01-27 | criteria provided, single submitter | clinical testing | The p.S63C variant (also known as c.188C>G), located in coding exon 4 of the BAP1 gene, results from a C to G substitution at nucleotide position 188. The serine at codon 63 is replaced by cysteine, an amino acid with dissimilar properties. In one study, this alteration was observed as a somatic alteration in a malignant pleural mesothelioma, and was demonstrated to have an increase in ubiquitin cleavage compared to wild-type BAP1 (Bott M et al. Nat. Genet. 2011 Jul;43(7):668-72). Another study found that this alteration retains its ability to be recruited to ionizing radiation induced DNA damage, and described this alteration as conferring a survival advantage (Ismail IH et al. Cancer Res. 2014 Aug;74(16):4282-94). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 5000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging yet tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV003642894 | SCV004432661 | uncertain significance | BAP1-related tumor predisposition syndrome | 2024-02-18 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the BAP1 protein (p.Ser63Cys). 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: 480816). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |