ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.783+2T>C (rs774730309)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485691 SCV000572190 likely pathogenic not provided 2018-03-19 criteria provided, single submitter clinical testing This variant is denoted BAP1 c.783+2T>C or IVS9+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 9 of the BAP1 gene. This variant has not, to our knowledge, been published in the literature. However, this variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Based on the currently available information, we consider BAP1 c.783+2T>C to be a likely pathogenic variant.
Color Health, Inc RCV000579423 SCV000682645 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-03 criteria provided, single submitter clinical testing This variant causes a T to C nucleotide substitution at the +2 position of intron 9 of the BAP1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with mesothelioma (PMID: 30338612) and breast cancer (PMID: 30980208; Color internal data). This variant has also been identified in 2/251252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BAP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV000818792 SCV000959424 likely pathogenic Tumor susceptibility linked to germline BAP1 mutations 2020-09-24 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the BAP1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs774730309, ExAC 0.002%). This variant has been reported in the literature in an individual with malignant pleural mesothelioma (PMID: 30338612). ClinVar contains an entry for this variant (Variation ID: 422670). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000579423 SCV001189319 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-26 criteria provided, single submitter clinical testing The c.783+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 9 in the BAP1 gene. This alteration has been reported in the literature in one individual diagnosed with malignant pleural mesothelioma, as well as in a large cohort of cancer patients (Betti M et al. Genes Chromosomes Cancer. 2018 11;57:573-583; Massengill JB et al. Genes Chromosomes Cancer. 2018 09;57:478-481). However, this alteration has also been observed in many individuals who do not have a personal or family history that is consistent with or suggestive of BAP1-associated disease (Ambry internal data; Bernstein-Molho R et al. Breast Cancer Res. Treat., 2019 Jul;176:165-170). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the native splice donor site efficiency. RNA studies have demonstrated that this alteration does not abolish the use of the native splice acceptor and low-level use of an upstream cryptic acceptor is predicted to lead to an in frame loss of amino acids with no known function (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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