Exploring the hereditary genetic mutational landscape of breast and ovarian cancer in Estonia

Germline genetic testing (GT) of cancer-associated genes enables the identification of hereditary risk in breast (BC) and ovarian cancer (OC) patients, supporting early diagnosis and personalized treatment strategies. In this study, we analyzed data from 3,537 patients who underwent routine clinical GT in Estonia between 2007–2023, including 2,856 BC and 759 cases of OC. A total of 78 individuals in the study were diagnosed with both BC and OC. The mean age at diagnosis and GT was 50.4 ± 12.0 and 54.0 ± 12.5 years for BC, and 56.1 ± 14.1 and 59.4 ± 13.3 years for OC, respectively. Non-genetic medical specialists ordered most GT (66.1%). GT increased nine-fold over the course of the study period. Altogether, 687 pathogenic/likely pathogenic variants (PV) were identified in 668 individuals (17.4% in BC, 26.0% in OC), with an overall combined PV detection rate of 18.9%. The most frequently mutated genes were BRCA1 (6.9% BC; 16.3% OC), BRCA2 (3.8%; 4.5%), and CHEK2 (3.5%; 1.7%). Two BRCA1 PV, c.5266dup and c.4035del, accounted for 29.1% of all PV detected. In addition to BRCA1/2, we identified 19 non-BRCA cancer susceptibility genes in 243 individuals and 25 novel PV, which demonstrates the importance of multi-gene NGS-based GT in Estonia for identifying hereditary cancer risk.