A pathogenic mutation in BRCA2 significantly increases the risk of breast and ovarian cancers making it imperative to examine the functional consequences of variants of uncertain clinical significance. Variants that are predicted to result in a truncated protein are unambiguously classified as pathogenic. We have previously shown how a pathogenic splice site variant known to generate a premature termination codon (PTC) in exon 9 and a nonsense mutation at exon 7, can generate functional BRCA2 by skipping exons 4-7 and restoring the reading frame. Using a well-established mouse embryonic stem cell-based assay, we functionally characterize here one splice site mutation and 11 pathogenic BRCA2 variants that are either nonsense mutation or generate PTC in different exons ranging from exons 4 to 7. Our study shows that five variants can restore the open reading frame by exon skipping and generate a functional protein. This suggests further need to exercise prudence when classifying clearly pathogenic variants.
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The research was sponsored by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health.
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Stauffer, S., Biswas, K. & Sharan, S.K. Bypass of premature stop codons and generation of functional BRCA2 by exon skipping. J Hum Genet 65, 805–809 (2020). https://doi.org/10.1038/s10038-020-0768-0