Impact on splicing of +2T variants of the breast cancer susceptibility genes

This dataset contains fragment analysis and sequencing files of the impact on splicing of +2T variants of the breast cancer susceptibility genes. Splicing dysregulation is a well-established mechanism of pathogenicity for variants in disease susceptibility genes. Variants at the critical intronic +1,2 GT nucleotides of the 5’ splice-site (5’ss) are considered strong signals of pathogenicity. However, some +2T variants create functional non-canonical 5’ss that generate wild-type transcripts, hampering accurate variant interpretation and genetic counselling. We investigated the functional impact of 29 +2T>N variants of the breast cancer susceptibility genes ATM, BRCA1 and PALB2 using minigene splicing assays. Six variants generated wild-type transcripts (4%-81% of the overall expression). As expected, high expression of wild-type transcripts significantly affected variant interpretation.