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BAP1  is a tumor suppressor gene that is lost or deleted in diverse cancers, including uveal mela¬noma, malignant pleural mesothelioma (MPM), clear cell renal carcinoma, and cholangiocarcinoma. Recently,  BAP1  germline mutations have been reported in families with combinations of these same cancers. A particular challenge for mutation screening is the classification of non-truncating  BAP1  sequence variants because it is not known whether these subtle changes can affect the protein function sufficiently to predispose to cancer development. Here we report mRNA splicing analysis on a homozygous substitution mutation,  BAP1  c. 2054 A&T (p.Glu685Val), identified in an MPM cell line derived from a mesothelioma patient. The mutation occurred at the 3rd nucleotide from the 3’ end of exon 16. RT-PCR, cloning and subsequent sequencing revealed several aberrant splicing products not observed in the controls: 1) a 4 bp deletion at the end of exon 16 in all clones derived from the major splicing product. The  BAP1  c. 2054 A&T mutation introduced a new 5’ splice site (GU), which resulted in the deletion of 4 base pairs and presumably protein truncation; 2) a variety of alternative splicing products that led to retention of different introns: introns 14–16; introns 15–16; intron 14 and intron 16; 3) partial intron 14 and 15 retentions caused by activation of alternative 3’ splice acceptor sites (AG) in the introns. Taken together, we were unable to detect any correctly spliced mRNA transcripts in this cell line. These results suggest that aberrant splicing caused by this mutation is quite efficient as it completely abolishes normal splicing through creation of a novel 5’ splice site and activation of cryptic splice sites. These data support the conclusion that  BAP1 c . 2054 A&T  (p.E685V) variant is a pathogenic mutation and contributes to MPM through disruption of normal splicing.

plos one

BAP1 Missense Mutation c.2054 A&gt;T (p.E685V) Completely Disrupts Normal Splicing through Creation of a Novel 5’ Splice Site in a Human Mesothelioma Cell Line