Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000798337 | SCV000937949 | pathogenic | BAP1-related tumor predisposition syndrome | 2020-10-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with mesothelioma, ocular melanoma, melanoma, and clear cell renal cancer (PMID: 30975761, 30414346, 30477459, Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the BAP1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Ambry Genetics | RCV001010385 | SCV001170577 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-16 | criteria provided, single submitter | clinical testing | The c.122+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the BAP1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Several close-match alterations at this donor site have been identified in individuals meeting diagnostic criteria for BAP1-related Tumor Predisposition Syndrome and at least one has been validated to cause aberrant skipping of exon 3 (Rao R et al. Retin Cases Brief Rep;12:1-4; Ewens KG et al. BMC Cancer, 2018 Nov;18:1172; Potjer TP et al. Int. J. Cancer, 2019 05;144:2453-2464; Chau C et al. Cancers (Basel), 2019 Aug;11:). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to date, this variant is interpreted as a disease-causing mutation. |