Germline pathogenic variant spectrum and prevalence among colorectal cancer patients undergoing multigene panel testing in Kazakhstan

Colorectal cancer (CRC) is a type of malignancy with a hereditary component. In Kazakhstan, the spectrum of germline pathogenic variants (PV) among individuals with CRC remains limited. In this study, multigene panel testing was performed on a Kazakhstani cohort of CRC patients and their relatives to better understand genetic risk factors. The study included 155 CRC patients and 92 healthy relatives. Whole coding regions (> 1700 exons) and flanking noncoding sequences of 94 cancer-associated genes were analyzed using the Illumina TruSight Cancer NGS panel on blood-derived DNA. Results showed that 30 patients (19. 4%) carried 31 PVs. Overall, 34. 2% of patients had a family history of cancer, including 9. 7% who had a family history of CRC. The most frequent germline PVs were in CHEK2 (22. 58%) and APC (12. 91%), followed by MLH1 (6. 46%), MSH2 (6. 46%), MSH6 (6. 46%), MUTYH (6. 46%), and BRCA1 (6. 46%). Missense (35. 5%) and frameshift (32. 3%) variants predominated. A high number of PVs was found in individuals aged 18–44 years. Among overall identified PVs, six were novel: APC c. 3405T > G, APC c. 419₄22delAGAG, PMS1 c. 1258delC, MLH1 c. 1291₁292delAT, NBN c. 877delA, and EPCAM c. 184 + 1G > A. The observed prevalence of clinically actionable PVs in both patients and their relatives highlights the potential clinical value of multigene panel testing and cascade screening strategies in Kazakhstan.