ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.281A>G (p.His94Arg)

dbSNP: rs1553645950
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571864 SCV000664707 likely pathogenic Hereditary cancer-predisposing syndrome 2024-10-17 criteria provided, single submitter clinical testing The p.H94R variant (also known as c.281A>G), located in coding exon 5 of the BAP1 gene, results from an A to G substitution at nucleotide position 281. The histidine at codon 94 is replaced by arginine, an amino acid with highly similar properties. This variant was identified in multiple individuals with a personal and/or family history of BAP1-associated disease (Ambry internal data; Walpole S et al. J Natl Cancer Inst, 2018 Dec;110:1328-1341; Repo P et al. Hum Mol Genet, 2019 Jul;28:2415-2426; Helgadottir H et al. Acta Oncol, 2023 Jun;62:565-570). This alteration was non-functional in a high throughput genome editing haploid cell survival assay (Waters AJ et al. Nat Genet, 2024 Jul;56:1434-1445). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001214123 SCV001385789 uncertain significance BAP1-related tumor predisposition syndrome 2019-08-08 criteria provided, single submitter clinical testing 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. This sequence change replaces histidine with arginine at codon 94 of the BAP1 protein (p.His94Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with uveal melanoma (PMID: 30517737). ClinVar contains an entry for this variant (Variation ID: 480852). This variant has been reported to affect BAP1 protein function (PMID: 31058963).
GeneDx RCV003328602 SCV004035798 uncertain significance not provided 2023-03-15 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate abolished deubiquitination ability, but retained nuclear localization (Repo et al., 2019); This variant is associated with the following publications: (PMID: 31058963, 30517737)

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