A targeted panel of actionable high-risk hereditary cancer predisposition genes to identify patients with pathogenic/likely pathogenic variants (PVs) irrespective of meeting established NCCN testing criteria.

10596 Background: Current germline cancer testing guidelines are limited to patients who meet specific personal and family cancer history (PH, FH) criteria. Our objective was to determine if differences in PV rates exist based on meeting National Comprehensive Cancer Network (NCCN) testing criteria in patients who underwent testing for known actionable genes. Methods: 29 genes with actionable NCCN management guidelines were evaluated. Consecutive patients (N=195,615) aged 18 to 100 years had hereditary cancer testing at a commercial laboratory at the ordering clinician’s discretion that included at least the 29 genes between June 2020 and August 2023. Per clinician-reported patient features (e.g. FH, PH, age), patients were categorized as meeting or not meeting current NCCN testing criteria for breast/ovarian/pancreatic (BOP v2.2024), and colorectal cancer (v1.2023). PV rates were calculated for all genes associated with breast, endometrial, ovarian, prostate, pancreatic, and colorectal cancer risk. Results: PVs were reported in 6634/105,194 (6.3%) patients that met the testing criteria and 5134/90,421 (5.7%) that did not. Of patients with a PV, 5134/11,768 (43.6%) did not meet NCCN testing criteria. When comparing patients with PVs based on NCCN testing criteria, patients were similar in age (median Q1, Q3, 43.6 35.0, 56.1 v 42.5 34.7, 56.6 years) and sex (female 91.5% v 91.3%). While PH and FH were comparable, a PH of cancer (31.5% v 36.1%, OR=0.81, 95% CI 0.75-0.88, p<0.001) and/or a FH of cancer (83.9% v 97.1%, OR=0.16, 95% CI 0.13-0.18, p<0.001) were slightly lower in patients who did not meet criteria compared to those who met testing criteria. On evaluating results in genes associated with individual cancer types, similar PV rates between the groups were observed (Table). Among all patients with PVs, the most common genes were CHEK2, BRCA1, BRCA2, and ATM. Most patients had only 1 PV reported (met: 96.5%, not met: 97.5%). Conclusions: In this cohort of patients who underwent germline testing, approximately 40% of patients with PVs in this study did not meet existing NCCN testing criteria. PV rates were similar between patients that met criteria and those that did not. Broadening existing testing criteria may reduce the number of patients who would otherwise be missed, thereby allowing for treatment decision-making and cascade testing of family members. Table: see text