Background: Pathogenic variants in CDH1 (CDH1+) are associated with hereditary diffuse gastric cancer (HDGC), with an increased risk for DGC (~40-83%) and lobular breast cancer (BC) (~64%) [1]. The National Cancer Center Network recommends the inclusion of CDH1 in multi-gene panel testing (MGPT) for patients with significant history of BC, given its classification as a high-risk BC gene [2]. Management includes prophylactic gastrectomy or consideration of annual endoscopic biopsies and high-risk breast screening, with consideration of prophylactic mastectomy. Several studies have identified CDH1+ patients who do not meet the International Gastric Linkage Consortium’s diagnostic criteria for HDGC [3.4,5,6]. These studies have brought concerns of CDH1 pathogenic variants in patients with low risk phenotypes, given the potential for total gastrectomy to reduce DGC risk. Our study aims to investigate our cohort of patients with a personal and/or family history of BC to determine if there is a significant number of CDH1+ patients with a non-classical presentation of HDGC. Methods: 17,208 families with a history of BC who underwent MGPT were seen in a Clinical Cancer Genetics (CCG) high-risk breast clinic between August 2013 and July 2022. They were identified using a prospectively maintained MD Anderson Cancer Center CCG database. Families were categorized by their history of GC and CDH1 status. Results: Among the families, 10,202 (59%) had a proband with a personal history of BC, with a mean age of onset of 51 years. 49 families (0.28%) were CDH1+. 21 CDH1+ families (43%) had no personal and/or family history of GC. Overall, 0.12% of families within the cohort were CDH1+ and had no family history of GC. A chi-square goodness of fit test was performed comparing observed (O) versus expected frequencies (E) (O/E) of families that were: 1) CDH1+ and had a history of GC (28/28), 2) CDH1+ and no history of GC (21/21), 3) CDH1 – (benign variant or variant of unknown significance (VUS)) and a history of GC (180/164), and 4) CDH1- and no history of GC (16,979/16,995). O was determined by using a general population risk of GC (0.81%) and estimated risk of DGC for CDH1+ individuals (58.2%). The X² was determined to be 1.576, with a p-value of 0.66483. Conclusions: In comparison to the expected frequency of incidental CDH1+ families identified via MGPT, we found that there was not a significant difference in expected and observed frequencies of families based on CDH1 status and presence of GC. These results likely reflect the incomplete penetrance and variable expressivity of HDGC, in addition to reported cases of occult signet ring cell carcinomas in biopsy samples or surgical pathology that has been reported in low risk presenting families [7]. We seek to validate these results with cohort of patients in which the diffuse gastric cancer pathology is known and to expand the analysis in patients specifically with a personal history of lobular breast cancer.