Submissions for variant NM_004656.4(BAP1):c.38-2A>G

dbSNP: rs2153228637

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001980500	SCV002274502	likely pathogenic	BAP1-related tumor predisposition syndrome	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with BAP1-related cancers (PMID: 35032816; internal data). ClinVar contains an entry for this variant (Variation ID: 1489173). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (internal data). 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	RCV002361358	SCV002623851	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	The c.38-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 2 in the BAP1 gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with BAP1-related disease (Ambry internal data). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is in-frame and is not expected to trigger nonsense-mediated mRNA decay (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV001980500	SCV004045452	likely pathogenic	BAP1-related tumor predisposition syndrome	2023-05-17	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004999593	SCV005625020	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	The BAP1 c.38-2A>G variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal BAP1 mRNA splicing. However, it is not expected to cause loss of protein expression through nonsense-mediated decay and may still disrupt protein function. This variant has been reported in the published literature in an individual with lung adenocarcinoma (PMID: 31721094 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV004999593	SCV005901019	likely pathogenic	not provided	2024-09-23	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in a patient with lung cancer (PMID: 31721094); This variant is associated with the following publications: (PMID: 31721094)