Characterization of spliceogenic variants located in regions linked to high levels of alternative splicing: BRCA2 c.7976+5G > T as a case study

Many BRCA1 and BRCA2 (BRCA1/2) genetic variants have been studied at mRNA level and linked to hereditary breast and ovarian cancer due to splicing alteration. In silico tools are reliable when assessing variants located in consensus splice sites, but we may identify variants in complex genomic contexts for which bioinformatics is not precise enough. In this study, we characterize BRCA2 c.7976 + 5G > T variant located in intron 17 which has an atypical donor site (GC). This variant was identified in three unrelated Spanish families and we have detected exon 17 skipping as the predominant transcript occurring in carriers. We have also detected several isoforms (Δ16‐18, Δ17,18, Δ18, and ▼17q224) at different expression levels among carriers and controls. This study remarks the challenge of interpreting genetic variants when multiple alternative isoforms are present, and that caution must be taken when using in silico tools to identify potential spliceogenic variants located in GC‐AG introns. In this study we characterize BRCA2 c.7976 + 5G > T variant located in intron 17, which has an atypical donor site (GC). The variant promotes exon 17 skipping, but several isoforms (Δ16‐18, Δ17,18, Δ18, and ▼17q224) have also been detected at different expression levels in variant carriers and controls. This study remarks the challenge of interpreting genetic variants located in regions with high levels of alternative splicing.