Multigene panel testing reveals the spectrum of non-BRCA germline variants in BRCA1/2-negative breast, ovarian, and prostate cancer patients from a Turkish cohort.

Targeted multigene panel testing is increasingly used to assess hereditary cancer susceptibility beyond BRCA1/2. However, the distribution and clinical significance of pathogenic variants and variants of uncertainsignificance (VUS) in non-BRCA1/2 genes remain incompletely characterized. In this retrospective study, 647 individuals referred for hereditary cancer genetic testing were analyzed. Clinical indications included breast cancer, ovarian cancer, combined breast and ovarian cancer, prostate cancer, andpositive family history without personal cancer diagnosis. Germline variants were classified according to ACMG/AMP guidelines as pathogenic (P), likely pathogenic (LP), VUS++, VUS, or benign/VUS. Variants categorizedas VUS or benign/VUS were not used for clinical decision-making. Pathogenic or likely pathogenic (P/LP) variants were identified in 16.2% (105/647) of individuals. When P/LP and VUS++ variants were considered together, the most frequently affected non-BRCA1/2 genes were CHEK2(4.0%), MUTYH (2.6%), ATM (2.2%), and TP53 (1.4%). VUS and benign/VUS variants were detected in 4.6% (30/647) and 3.1% (20/647) of individuals, respectively. CHEK2 and ATM were the genes most frequentlyassociated with VUS or benign/VUS variants. Breast cancer was the most common clinical indication among individuals carrying clinically relevant variants. Non-BRCA1/2 genes, particularly CHEK2 and ATM, substantially contribute to the spectrum of pathogenic variants detected in hereditary cancer testing. The identification of numerous pathogenic and novel variantssupports the clinical utility of broad multigene panel testing, while highlighting the need for careful interpretation of VUS in clinical practice.