Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001040249 | SCV001203811 | pathogenic | BAP1-related tumor predisposition syndrome | 2022-07-18 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26719535). ClinVar contains an entry for this variant (Variation ID: 838659). Disruption of this splice site has been observed in individual(s) with malignant mesothelioma (PMID: 26719535). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 14 of the BAP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BAP1 are known to be pathogenic (PMID: 21874000, 23684012). |
| Color Diagnostics, |
RCV001183439 | SCV001349159 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-09-22 | criteria provided, single submitter | clinical testing | This variant causes a G to A nucleotide substitution at the canonical -1 position of intron 14 of the BAP1 gene. Splice site prediction tools suggest that this canonical splice site variant may have a significant impact on RNA splicing. This variant has been reported in an individual affected with malignant mesothelioma at age 47 (PMID: 26719535). The proband's father with non-Hodgkin's lymphoma and his sister with thyroid cancer were diagnosed with a malignancy at a relatively young age, at age 52 and 34, respectively. A mini-gene splice study has reported that this variant results in the retention of a portion of intron 14 sequence in the mRNA from the use of an alternative, cryptic splice site within intron 14, and this was predicted to cause a frameshift and premature truncation of the translated BAP1 protein (PMID: 26719535). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BAP1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Ambry Genetics | RCV001183439 | SCV002723874 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-03 | criteria provided, single submitter | clinical testing | The c.1891-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 15 of the BAP1 gene. This alteration has been identified in 1/150 individuals diagnosed with malignant mesothelioma and a family history of cancer (Ohar JA et al. Cancer Res., 2016 Jan;76:206-15). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing; however, this alteration leads to the use of a naturally occurring alternate splice acceptor site leading to the in-frame insertion of 23 amino acids with unknown function (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV001040249 | SCV004214920 | pathogenic | BAP1-related tumor predisposition syndrome | 2023-01-16 | criteria provided, single submitter | clinical testing |