Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations.

摘要: Several unclassified variants (UVs) have been identified in splicing regions of disease-associated genes and their characterization as pathogenic mutations or benign polymorphisms is crucial for the understanding role disease development. In this study, 24 UVs located at BRCA1 BRCA2 splice sites were characterized by transcripts analysis. These results used to evaluate ability nine bioinformatics programs predicting genetic causing aberrant (spliceogenic variants) nature transcripts. Eleven 8 BRCA2, including not previously transcript level, ascertained affect mRNA splicing. Of these, 16 led synthesis containing premature termination codons (PTCs), 2 up-regulation naturally occurring alternative PTCs, one an in-frame deletion within region coding DNA binding domain loss bind partner protein DSS1 ssDNA. For each computational program, we evaluated rate non-informative analyses, i.e. those that did recognize natural wild-type sequence, false positive predictions, i.e., incorrectly classified spliceogenic, a measure specificity, under conditions setting sensitivity predictions 100%. The performed better Human Splicing Finder Automated Splice Site Analyses, both exhibiting 100% informativeness specificity. 10 activation cryptic was observed, but unable derive simple criteria select, among different predicted actually used. Consistent with previous reports, our study provides evidences silico tools can be selecting site vitro analyses. However, latter remain mandatory