Analysis of cancer predisposition and functional analysis of variants of unknown significance

On average, 5-10% of all cancers occur in patients with hereditary tumors, who may have mutations in tens to hundreds of tumor predisposition genes. The phenotypes in mutation carriers overlap, and parallel analyses with sequencing panels is the method of choice in diagnostics. In our laboratory, we designed a universal panel and a targeted panel for a specific cancer, which allowed us to identify genetic alterations in patients with ovarian cancer, breast cancer, melanoma, and other cancers in the Czech Republic. The results of next generation sequencing (NGS) analyses show that the most frequent genetic alteration in ovarian cancers patients in the Czech Republic are hereditary mutations in BRCA1 (in 24% of unselected patients) and in malignant melanoma patients CDKN2A (in 2% of high risk patients). The presence of hereditary alterations is a clinically significant phenomenon affecting the prognosis and treatment of the disease. However, the interpretation of NGS findings is complicated by the presence of variants of unknown significance (VUS). We participate in the interpretation of VUS in the main predisposing genes BRCA1 and BRCA2 within the international consortium ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles). Our and international results of the most..