Klin Onkol 2006; 19(Suppl): 58-62.
Abstract
In clinical practice only true pathogenic disease causing mutations can be used as an output of molecular genetic testing. Underestimating of total number of pathogenic mutations detected during BRCA1 and BRCA2 genes mutation screening might be due to existence of sequence variants of unknown significance. The group of 25 unknown variants found in probands from high-risk families with hereditary breast and/or ovarian cancer syndrome was examined. After consequent analysis six pathogenic splice site mutations and four polymorphic variants without an effect on cancer predisposition were determined. Differentiating of pathogenic mutations from common benign polymorphisms is very important for genetic counseling.
The presence of large intragenic rearrangements commonly overlooked by PCR-based screening techniques is supposed to be another reason for lower prevalence of pathogenic mutations in high-risk families. MLPA analysis was performed in 152 unrelated patients with hereditary breast and/or ovarian cancer syndrome which were negative after complete screening of coding regions of BRCA1/2 genes. Six different large intragenic deletions in BRCA1 gene were identified in nine of high-risk families. Using MLPA the total number of detected BRCA1 mutations were increased about 8%.
