10611 Background: Although most endometrial cancers (EC) are sporadic, 2–6% arise in the setting of Lynch syndrome (LS) or Cowden syndrome. The prevalence and clinical correlates of other germline pathogenic/likely pathogenic variants (PVs) remain incompletely characterized. We assessed the prevalence of potentially actionable germline PVs in EC and their clinicopathologic associations. Methods: This retrospective cohort included 3,844 EC patients (pts) who underwent pan-cancer germline multigene panel testing at a single diagnostic laboratory (2018–2025). Pts < 18 years, with mosaic results, or unclear pathology were excluded. Clinical and pathologic variables were compared between pts with and without PVs using appropriate statistical methods, including multivariable logistic regression. Results: The final cohort comprised 3,693 females; 46.6% were non-Hispanic White and 8.3% African American. Median age at testing was 62 years and median age at diagnosis was 57 years. Overall, 20.8% (n = 804) harbored a PV in a high- or moderate-penetrance gene. Among 852 PVs identified, 46.9% occurred in DNA damage response (DDR) genes, 37.0% in LS genes, and 16.1% in other genes. The most frequent DDR PVs were BRCA2 (12.6%), CHEK2 (9.2%), BRCA1 (8.0%), ATM (7.5%), PALB2 (3.1%). PTEN accounted for 3.2% of the PV. PV carriers were younger at testing (60 vs 62 years; p = 0.014) and diagnosis (54 vs 57 years; p < 0.001), more often African American (12.4% vs 7.2%; p < 0.001), and had higher rates of colorectal cancer (7.7% vs 3.4%; p < 0.001) and multiple primary cancers (41.7% vs 36.8%; p = 0.012). In multivariable analysis, younger age at EC diagnosis (OR 0.99; p = 0.028) and personal history of colorectal cancer (OR 1.84; p < 0.001) remained independently associated with PV status. Histologic subtype distribution differed between LS and DDR groups (p < 0.001); endometrioid tumors were more frequent in LS (26.6% vs 22.7%), whereas serous carcinoma (7.3% vs 1.1%) and carcinosarcoma (4.2% vs 1.8%) were more frequent in DDR. Among pts with available immunohistochemical (IHC) data (n = 810), 51.2% (n = 415) showed mismatch repair protein loss. Of these, 96 (23.1%) had PVs in LS genes, 13 (3.1%) in DDR genes, and 9 (2.2%) in other genes; 297 (71.6%) had no germline PV. Notably, among 161 pts with MLH1/PMS2 loss and confirmed MLH1 promoter methylation, 25 (15.5%) still harbored PVs; 4 (2.5%) in LS genes, 16 (9.9%) in DDR genes and 5 (3.1%) in other genes. Conclusions: Germline PVs were identified in over 20% of EC cases, extending beyond LS or Cowden syndrome. The presence of PVs in MLH1 -methylated tumors—traditionally considered sporadic—is a critical finding that challenges current tumor-only triage. These results support universal multigene germline testing in EC. A complementary case–control analysis including cancer-free controls and an independent validation cohort will be presented.
Hernandez et al. (Wed,) studied this question.