Introduction/Background*Implementation of NGS panel sequencing (instead of single/double gene/s sequencing) into standard genetic testing for cancer susceptibility generates new and unexpected data on spectrum, proportion and combination of susceptibility genes´ mutations.

Methodology We analyzed results of genetic testing in healthy patients referred to our survailance office, their pedigrees and clinical manifestations to identify and describe clinical meaning of combined heterozygosity in different cancer suceptibility genes. We also discusse prophylactic measures in these double heterozygotes.

Result(s)*In the group of 455 individuals who underwent genetic testing for known or suspicious genetic susceptibility to cancer, we identify 11 (2.4%) double heterozygotes, i.e. individual harbouring germ-line pathologic mutations in two high penetrance susceptiblity genes. 8 of them have mutations in either BRCA1/2 genes and mismatch-repair genes (MLH1 or MSH2), 3 remaining have combination of BRCA1 mutation and RAD51, VHL and CHEK2, respectivelly. 3 out of 11 double heterozygotes developer cancer through median follow-up of 34 moths, 2 breast cancer, 1 colorectal cancer. Pedigree analysis does not allow for individualisation of risk calculation.

Conclusion*Double heterozygotes are known from literature, till the era of NGS panel sequencing, they wer thought to be extremelly rare. These individuals, however, represent a substantional proportion of our patients and need individualised scenario of survailance with respect to different spectrum of risks compared to single mutation carriers.