Prevalence of <i>CDH1</i> germline variants in gastric cancer patients with exome-inferred ancestry.

4073 Background: Germline pathogenic or likely pathogenic (P/LP) CDH1 variants increase the lifetime risk of developing diffuse gastric cancer (DGC). Given that the epidemiology and prognosis of gastric cancer vary based on patient ancestry, and Hispanic and Black/African-American patients have been underrepresented in clinical and translational research, we sought to determine the prevalence of CDH1 variants in a diverse population of gastric cancer patients. Methods: Germline whole exome sequencing (WES) data from gastric cancer patients were obtained as part of commercial ordering of personalized circulating tumor DNA testing (Signatera, Natera, Inc.) from March 2024 to June 2025. Ancestry was inferred by EthSeq and classified into predefined groups: European (EUR), admixed American (AMR), African (AFR), and East Asian (EAS). Germline single-nucleotide variants and short insertions/deletions were identified and annotated with Variant Effect Predictor (v.105), and the pathogenicity of variants in CDH1 was determined using classifications available in the ClinVar database. The prevalence of P/LP variants and variants of uncertain significance (VUS) were compared across ancestries. Potential pathogenicity of VUS was evaluated using in silico predictors SIFT (v5.2.2), Polyphen (v2.2.2), and AlphaMissense (hg19). Results: Among 2,567 patients, 55% (1,414/2,567) were male and the median age was 67 years. Ancestry inference identified 47% (n=1,201) as EUR, 22% (n=575) as AMR, 18% (n=457) as AFR, and 13% (n=334) as EAS. Patients with AMR ancestry were younger compared to EUR ancestry patients (median 62 years vs 69 years; adj p&lt;0.0001), and less likely to be male (51% [295/575] vs. 58% [693/1201]; OR, 0.7; 95% CI, 0.63–0.94; p=0.015). No significant differences in age or sex were observed in patients with AFR (median 68 years, 55% male) or EAS (median 68 years, 52% male) ancestry compared to EUR. Overall, 0.7% (n=17) gastric cancer patients had a P/LP variant, and there was no difference across ancestries (0.8% of EUR, 0.5% of AMR, 0.4% of AFR, and 0.6% of EAS patients). We found that 1.1% (n=27) of the cohort had a CDH1 VUS, the rate for which did not vary across ancestries (1.2% of EUR, 0.52% of AMR, 0.84% of AFR, 0.60 of EAS). Of the 21 unique VUS, 33% (n=7) were each predicted to be pathogenic by all three in silico predictors. One unique VUS was observed in two unrelated patients: NM_004360.5:c.635G&gt;T (p.Gly212Val). The predicted-pathogenic VUS were similarly distributed across ancestries. Conclusions: This real-world analysis highlights that CDH1 VUS were similarly distributed across ancestries. Notably, we found that one-third of VUS identified were predicted to have pathogenic function across three in silico prediction tools. This highlights the need for functional assays to determine the variant biology to improve gastric cancer risk assessment.