Germline genetic testing for hereditary cancer syndromes among newly diagnosed patients with solid tumors: A report of 10,000 patients from the Jordanian Exploratory Cancer Genetics study.

10592 Background: Hereditary factors play a key role in the risk of developing several cancers. Identification of germline cancer predisposing genes can have important implications for cancer screening, risk-reduction, risk-reducing interventions, and treatment decisions. Methods: In this study, patients with various cancers diagnosed and treated at King Hussein Cancer Center (KHCC) between January 2014 and December 2024 who had germline genetic testing (GGT) were retrospectively reviewed. Most patients were tested as per the National Comprehensive Cancer Network (NCCN) guidelines for GGT, while 3,319 patients were tested as part of a study for universal testing of all newly diagnosed cancer patients. Genetic testing was performed at reference commercial laboratories, or at academic centers. Results: The study involved 9,872 patients, the mean age at diagnosis was 49.7 (range: 18-90) years. Breast cancer was the most prevalent cancer type, comprising 67.3% of all cases, followed by colorectal cancer at 11.5%. Pathogenic/likely pathogenic (P/LP) variants were detected in 1,007 (10.2%) of the patients, while variants of uncertain significance (VUS) accounted for 33.6% of all genetic test results, highlighting the challenges of expanded panel testing. The most frequently identified pathogenic genes were BRCA1 and BRCA2, with 197 (2.0%) and 333 (3.4%) P/LP variants detected, respectively. Other notable genes included CHEK2 (n=28), PALB2 (n=38) and TP53 (n=47). Breast and colorectal cancers showed the highest number of pathogenic variant detections, with breast cancer accounting for 66.3% of all P/LP cases. Among less common cancers, ovarian cancer demonstrated a relatively high pathogenic variant rate (21.9%) despite its lower overall prevalence. Testing eligibility played a significant role in outcomes, with the majority of patients undergoing guideline-based testing (60%) and 26% undergoing universal testing. Expanded testing panels increased the detection of VUS significantly but did not improve pathogenic variant detection rates compared to guideline-based testing (p<0.001). There was also a significant association between cancer type and genetic testing results (p<0.001), underscoring the importance of cancer-specific testing strategies. Conclusions: These findings highlight the high prevalence of pathogenic variants in breast and colorectal cancers, the clinical relevance of BRCA1/2 and other high-risk genes, and the trade-offs of expanded genetic testing panels in balancing broader detection capabilities with interpretive challenges due to increased VUS rates. This emphasizes the need for targeted genetic counseling and strategic use of comprehensive testing panels for optimal clinical impact.