Submissions for variant NM_004656.4(BAP1):c.2056+1G>C

dbSNP: rs1578218644

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000818690	SCV000959316	likely pathogenic	BAP1-related tumor predisposition syndrome	2023-04-14	criteria provided, single submitter	clinical testing	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. Variants that disrupt 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. ClinVar contains an entry for this variant (Variation ID: 661302). Disruption of this splice site has been observed in individuals with clinical features of BAP1 tumor predisposition syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 16 of the BAP1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Color Diagnostics, LLC DBA Color Health	RCV001805895	SCV002053230	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +1 position of intron 16 of the BAP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The variant may result in the skipping of exon 16, creating a frameshift and premature translation stop signal, and resulting in a non-functional protein product. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Ambry Genetics	RCV001805895	SCV002727579	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-08-12	criteria provided, single submitter	clinical testing	The c.2056+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 16 of the BAP1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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. Although the predicted transcript is not expected to undergo NMD, alterations that produce transcripts with similar predicted protein effects have been identified in families with BAP1-associated disease and have been show to segregate among the affected family members. These include BAP1 c.2050C>T (p.Q684*) which encodes an NMD-escaping transcript leading to loss of the last two amino acids of exon 16 and the entirety of exon 17 (Rai K et al. Genes Chromosomes Cancer, 2017 02;56:168-174; Testa JR et al. Nat. Genet., 2011 Aug;43:1022-5; Carbone M et al. J Transl Med, 2012 Aug;10:179; Pilarski R et al. Genes Chromosomes Cancer, 2014 Feb;53:177-82); and BAP1 c.2057-2A>G which is at the acceptor site for exon 17, which is the last exon in BAP1. It leads to intron 16 retention which subsequently encodes a premature stop codon and loss of the last coding exon of BAP1 (Wiesner T et al. Nat. Genet., 2011 Aug;43:1018-21). Based on the majority of available evidence to date, this variant is likely to be pathogenic.