Frequency of variants of hereditary cancer risk syndrome in 1682 Brazilian patients genotyped by next-generation sequencing

Hereditary cancer risk syndromes are a group of disorders caused by germline variants in a growing number of genes. Most studies on hereditary cancer have been conducted in white populations. Here we report the largest study in Brazilian individuals with multiple, self-reported, ethnicities. We genotyped 1682 individuals from all regions of the country who were referred to genetic testing for hereditary cancer risk with multigene Next-generation sequencing (NGS) panels. Most were women, and had a personal and/or family history of cancer. The majority of cancer cases were breast and ovarian. We identified a total of 321 pathogenic/likely pathogenic (P/LP) variants in 305 people (18.1%), corresponding to 166 unique variants. These variants were distributed among 32 genes, and most were detected on BRCA1 and BRCA2 (129 patients, 26.2% and 14.3% of all P/LP hits, respectively). The prevalence of any genes transheterozygosity in our sample was 0.89% (15/1682). The BRCA1/BRCA2 double heterozygosity rate was 0.78% (1/129) for BRCA variants carriers and 0.06% (1/1682) overall. We classified patients according to the NCCN and Brazilian National Health Agency (ANS) genetic testing recommendation criteria. We found that the criteria had false negative rates of 17.3% and 44.2%, meaning that both failed to detect a substantial part of P/LP positive patients. Therefore, our results show that NGS adds to knowledge on the Brazilian spectrum of germline variants associated with cancer risk and indicate that Brazilian testing guidelines should be improved.