engleski

In Silico Analysis of BRCA1 and BRCA2 Sequence Variants of Unknown Clinical Significance: Application to Variants Found in Healthy Women in Croatia

BRCA1 and BRCA2 are the major hereditary breast and/or ovarian cancer predisposing genes and their mutations increase the risk of developing cancer. At present, almost half of all BRCA1 and BRCA2 sequence variants found are unclassified variants (UVs) so their clinical significance is unknown or uncertain. That represents problem for risk assessment in genetic counselling. After revealing BRCA1 and BRCA2 sequence variants in healthy Croataian females, our aim was to find fast in silico method for assessing preliminary clinical significance of UVs newly found in patients. We used different publicly available programs and web-based tools to identify UVs that may have deleterious effects with respect to different biomolecular functional categories (splicing regulation, transcriptional regulation, nonsynonymous amino acid SNP effect… ) so their clinical significance in cancer etiology could be assumed. Using straightforward physical and comparative considerations, we have found that several sequence variants with nonsynonymous amino acid change could have possible impact on the structure and function of a BRCA1 and BRCA2 proteins. Synonymous amino acid changes (silent mutations) could have impact on splicing regulation by disrupting exonic splice enhancers. Intronic sequence variants showed no potential impact on splicing because nucleotide changes at that positions likely make no changes in consensus splice sites. In Silico analysis of BRCA1 and BRCA2 presents fast, easy and cheap method for assessing preliminary clinical significance for UVs, especially in cases with low frequency and ethnic specific alleles, when it is difficult to make population based studies and when expensive experimental functional assays must be performed.

BRCA1 ; BRCA2 ; unclassified variants

nije evidentirano