ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.256-3C>A (rs752536342)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532965 SCV000651882 uncertain significance Tumor susceptibility linked to germline BAP1 mutations 2020-10-01 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the BAP1 gene. It does not directly change the encoded amino acid sequence of the BAP1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BAP1-related disease. ClinVar contains an entry for this variant (Variation ID: 472695). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. 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 Health, Inc RCV000580289 SCV000682615 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-26 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000722041 SCV000853218 likely pathogenic Ewing sarcoma 2017-08-24 criteria provided, single submitter clinical testing This is a splice site alteration in which a C is replaced by an A in intron 4, three nucleotides upstream of exon 5. Classification criteria: PVS1 (Although this alteration is not in a canonical +/- 1 or 2 splice site, examination of the patient's paired tumor transcriptome data revealed that this alteration is associated with abberant splicing and intron retention), PM2.
Ambry Genetics RCV000580289 SCV001176858 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing The c.256-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 5 in the BAP1 gene. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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