A novel missense mutation c.1381T>C: p.(S461P) in POLE causes multiple molecular features of endometrial carcinoma in China: A case report

Yingxue Li¹Li Wang^1,2Lin Han¹Zheng Zheng^1*Jinqiang Yan¹

• ¹Liaocheng People's Hospital, Liaocheng, China
• ²Liaocheng University, Liaocheng, China

Background: Accurately determining the pathogenicity of newly discovered POLE mutations is crucial for the precise molecular classification of endometrial carcinoma. Methods: In one patient with endometrial carcinoma, next-generation sequencing (NGS) was performed to detect variants in POLE, TP53, BRCA1/2, CTNNB1, EPCAM, MLH1, MSH2, MSH6, and PMS2, as well as microsatellite instability (MSI) status in the tumor tissues. Variant interpretation followed ACMG/AMP guidelines, integrating evidence from literature, established guidelines, public databases, and clinical studies. Immunohistochemistry was used to evaluate MLH1, PMS2, MSH2, MSH6, and p53 protein expression in tumor tissues. Results: We successfully identified a novel potential missense mutation, c.1381T>C: p.(S461P), in exon 14 of POLE. This variant, reported here for the first time in endometrial carcinoma, was preliminarily classified as likely pathogenic based on available evidence. Additional variants were detected: TP53: c.844C>T: p.(R282W), TP53: c.711G>A: p.(M237I), and MSH6: c.3103C>T: p.(R1035*). The MSI status was classified as MSI-L. Immunohistochemistry revealed MLH1 (+), PMS2 (+), MSH2 (+), MSH6 (−), and p53 expression consistent with a mixed pattern (80% tumor region wild type, 20% region mutant subtype). Conclusion: This is the first report of the POLE (c.1381T>C: p.(S461P)) variant in endometrial carcinoma. We analyzed its potential pathogenic mechanism, which may contribute to the complex molecular phenotype of POLEmut + MMRd + p53abn tumors, and expanded the POLE mutation spectrum by adding a new likely pathogenic site.