Abstract Background The Cancer Genome Atlas identified four molecular subgroups of endometrial cancer with survival differences based on whole genome, transcriptomic, and proteomic characterization. Clinically accessible algorithms that reproduce this data are needed. Our aim was to determine if targeted sequencing alone allowed for molecular classification of endometrial cancer. Methods Using a custom-designed 156 gene panel, we analyzed 47 endometrial cancers and matching non-tumor tissue. Variants were annotated for pathogenicity and medical records were reviewed for the clinicopathologic variables. Using molecular characteristics, tumors were classified into four subgroups. Group 1 included patients with > 570 unfiltered somatic variants, > 9 cytosine to adenine nucleotide substitutions per sample, and < 1 cytosine to guanine nucleotide substitution per sample. Group 2 included patients with any somatic mutation in MSH2, MSH6, MLH1, PMS2. Group 3 included patients with TP53 mutations without mutation in mismatch repair genes. Remaining patients were classified as group 4. Analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, North Carolina, USA). Results Endometrioid endometrial cancers had more candidate variants of potential pathogenic interest (median 6 IQR 4.13 vs. 2 IQR 2.3; p < 0.01) than uterine serous cancers. PTEN (82% vs. 15%, p < 0.01) and PIK3CA (74% vs. 23%, p < 0.01) mutations were more frequent in endometrioid than serous carcinomas. TP53 (18% vs. 77%, p < 0.01) mutations were more frequent in serous carcinomas. Visual inspection of the number of unfiltered somatic variants per sample identified six grade 3 endometrioid samples with high tumor mutational burden, all of which demonstrated POLE mutations, most commonly P286R and V411L. Of the grade 3 endometrioid carcinomas, those with POLE mutations were less likely to have risk factors necessitating adjuvant treatment than those with low tumor mutational burden. Targeted sequencing was unable to assign samples to microsatellite unstable, copy number low, and copy number high subgroups. Conclusions Targeted sequencing can predict the presence of POLE mutations based on the tumor mutational burden. However, targeted sequencing alone is inadequate to classify endometrial cancers into molecular subgroups identified by The Cancer Genome Atlas.