<h3>Objectives:</h3> To describe somatic mutations within the tumor genome of Black and Hispanic women with endometrial cancer of various grades and histologies. <h3>Methods:</h3> In 2019 at the University of Miami, 49 women with newly diagnosed endometrial cancer and undergoing hysterectomy were consented for a pilot study evaluating the association between tumor mutations detected in cervicovaginal secretions and somatic tumor mutations. Race and ethnicity were self-reported according to the U.S. Census Bureau categories. Cervicovaginal samples were collected by the surgeon immediately prior to vaginal prep and sent for microbial culture and whole exome sequencing (WES) analysis. Fresh tumor obtained at the time of surgery were flash-frozen, underwent DNA extraction and were similarly submitted for WES followed by concordance analysis compared to cervicovaginal specimens. WES somatic deleterious variants were identified by Polyphen and SIFT scores. Descriptive statistics including Chi-squared, Fisher' exact test and Mann Whitney U tests were used for analyses, with a threshold for significance of p<0.05. <h3>Results:</h3> Of the 49 women who enrolled, 40.8% were Black (n=20) and 55.1% were White (n=27). 38.8% were of Hispanic ethnicity (n=19). Relative to White patients, Black patients had a higher median number of in-frame insertions (3 [1.3, 5.5] vs 1 [0, 2], p=0.008), missense mutations (82.5 [64, 128.3] vs 37 [21, 72], p=0.01) and total mutations (96 [71.5, 141.8] vs 43 [25, 81], p=0.01 (Table 1). There were no significant differences in mutational variant types or total mutations between Hispanic and non-Hispanic women (Table 2).Several of the mutations which occurred most frequently in the study group[PA2] are previously unstudied in endometrial cancer including <i>TTN, LRP2, SACS, FLG2, RYR2 and MACF1</i>. Among Black patients, 3 <i>BRCA1</i> mutations (2 serous, 1 low-grade endometrioid) and 1 <i>BRCA2</i> mutation (small cell carcinoma) were identified. 4 <i>PTEN</i> mutations occurred and exclusively in low-grade tumors. <i>PIK3CA</i> was mutated in 2 low-grade tumors and 1 high-grade tumor. 2 <i>ARID1A</i> mutations were identified in low-grade tumors. <i>FBXW7</i> was mutated in 3 low-grade and 2 high-grade tumors. Multiple mismatch repair (MMR) pathway mutations were identified, affecting 4 Black patients. In Hispanic patients, there were no <i>BRCA1</i> or <i>BRCA2</i> mutations present. 5 <i>PTEN,</i> 2 <i>PIK3CA,</i> 5 <i>ARID1A</i> and 1 <i>FBXW7</i> mutations were identified and all were limited to low-grade tumors. Only one Hispanic patient with an MMR mutation (PMS2) was identified.The differences in the frequencies of these mutations did not reach statistical significance when comparing either White and Black or Hispanic and non-Hispanic women. <h3>Conclusions:</h3> A number of previously unstudied somatic mutations in endometrial cancer were identified in this cohort. Mutational variant type, but not gene frequency, varied significantly by race and ethnicity. Larger cohorts with extensive genetic and clinical outcomes data are needed to assess the clinical significance of these findings.