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Background: Endometrial serous carcinoma (ESC) and tubo-ovarian high-grade serous carcinoma (HGSC) are characterized by late-stage presentation and high mortality. Current guidelines for prevention recommend risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary mutations in cancer susceptibility genes. However, HGSC displays extensive genetic heterogeneity with alterations in 168 genes identified in TCGA study, but current germline testing panels are often limited to the handful of recurrently mutated genes, leaving families with rare hereditary gene mutations potentially at-risk., Objective: To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA)., Methods: We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA., Results: We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses., Conclusion: Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. One of the authors (RE) is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Gynecologic oncology] and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KMF has received honoraria as a speaker for Illumina – unrelated to the current manuscript; RE receives/has received research funding from Clovis oncology, GSK, Merck and AstraZeneca – unrelated to the current manuscript; RE has received consulting fees and/or honoraria from AstraZeneca, Clovis, Eisai, GSK, Daiichi Sankyo, PMV Pharmaceuticals, Immunogen, Mersana, Myriad, Novocure, Onconova, Elevar therapeutics and Renegenron – unrelated to the current manuscript. WS has received honoraria from Guardant Health – unrelated to the current manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)