In silico analysis of potential structural and functional significance of human breast cancer gene BRCA2 sequence variants found in 5' untranslated region

摘要

Background and Purpose: BRCA1 and BRCA2 are major hereditary breast/ovarian cancer predisposing genes and their mutations increase the risk of developing cancer. Genetic testing of these two genes is nowadays commonly performed but almost half of found genetics alterations are declared as variants of unknown clinical significance. Interpretation of these unclassified variants is the major concern for BRCA genes. The aim of this study is to investigate potential structural and functional significance of sequence variants found in 5' untranslated region (UTR) of BRCA2 gene. Materials and Methods: Consensus secondary structure of BRCA2 5’ UTR was built based on nucleotide sequences from four different species. We collected all found human BRCA2 5’ UTR variants and explored their potentials effects by folding human BRCA2 5’ UTR including one of each variant, using consensus structure as a constraint. If constrained folding results in a structure that is very different from the consensus one, this may indicate that this particular sequence variant could have potential functional impact. Results: Most of the sequence alterations are found near the 3’ end of 5’ UTR, what is in the vicinity of the translation initiation site. Four of them: c.-26GA, c.-26GC, c.-26GT and c.-12TC most notably disturbed consensus secondary structure by creating substructures with lower minimum free energy, thus less stable. Conclusions: As previously deduced in the case of variant c.-26GA, changes c.-26GC, c.-26GT and c.-12TC could unstabilize the loop at the vicinity of the translation start site, which could increase the efficiency of the translation and thereby increase the expression of BRCA2. Accordingly, our study suggests this three BRCA2 5’ UTR sequence variants as suitable candidates for further functional characterization and thus potentially clinically significant.