INTRODUCTION: A small proportion of clinicopathologically low-risk endometrial cancer (EC) patients who omitted adjuvant radiotherapy (RT) may subsequently develop a local recurrence. Molecular profile for those clinically low-risk yet recurred EC patients is unavailable. METHODS: A total of 442 EC patients treated from 2014 to 2020 at Northwestern Memorial Hospital were studied. Among them, 28 patients clinically low risk or low-intermediate risk per GOG-99 criteria developed an isolated local recurrence after hysterectomy, bilateral salpingo-oophorectomy, and omitted RT. Whole exome sequencing (WES) was performed on 22 patients whose pathologic specimen were retrievable. RESULTS: The majority of the cases studied were molecularly No Specific Molecular Profile (NSMP) cohort (91%). We identified CTNNB1, FGFR2, PTEN, and KRAS as the most frequently altered pathogenic or likely pathogenic genes with 5 (22.7%), 5 (22.7%), 4 (18.2%), and 3 (13.6%) out of 22 patients carrying these alterations, respectively. TP53 somatic alterations were identified in 2 (9.1%) out of 22 cases. Analysis of The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) dataset identified 53 EC patients with pathologically Grade 1 molecularly NSMP cohort. Within this cohort, CTNNB1 alterations were identified in 31 patients (58%) and prognosticated worse progression free survival (p<
0.05). CONCLUSION: NSMP molecular group constitutes the majority of clinically low-risk EC patients with isolated local recurrences. The CTNNB1 alteration was validated as a biomarker in prognostication in this independent cohort and may help guide adjuvant treatment decisions.