Abstract Background: Germline mutations in CDH1 are well-established as risk factors for hereditary lobular breast cancer (BC). However, the frequency and phenotypic landscape of CDH1 germline mutations in unselected BC populations remain incompletely defined. Here, we investigated the prevalence of CDH1 pathogenic/likely pathogenic (P/LP) germline variants in a large real-world BC cohort. Methods: We analyzed germline whole-exome sequencing (WES) data from 53,607 BC patients in Natera's Real-World Database. CDH1 variants were annotated using Ensembl Variant Effect Predictor (VEP). Variants classified as “LOW” impact (synonymous or non-functional splice region variants) were excluded. Germline P/LP classification was sourced from ClinVar. In the absence of ClinVar annotation, truncating variants were designated as P/LP. Ancestry inference was determined using the EthSeq algorithm with four groups: African (AFR), East Asian (EAS), European (EUR), and South Asian (SAS). Global variant frequencies were also compared using 1000 Genomes Project data. Results: Among the 53,607 BC patients analyzed, the majority had ductal histology (68.55%), followed by lobular (10.36%), mixed (2.78%), and not available (18.31%). The median age in the cohort was 57 range: 20-102. Prevalence of germline CDH1 variants meeting the inclusion criteria was 11.0% (5892/53607) globally, with 10.9%, 11.9%, 7.7%, and 8.8% prevalence in EUR, AFR, EAS, and SAS populations, respectively. By histology, 11.1% of lobular and 11.7% of ductal cases presented a CDH1 germline variant. We observed 367 unique CDH1 allele variants, with 19 classified as P/LP. These included three splice acceptor site variants, twelve variants within the extracellular protein domain, one in the transmembrane domain, and three within the cytoplasmic domain. P/LP CDH1 variants were found in 23 individuals, representing 0.39% of patients with CDH1 germline variants and 0.25% of all patients with lobular breast cancer (0.042% of all BC patients analyzed). Among the patients with P/LP variants, 14 had lobular, 7 ductal, and 2 unknown histologies, with a median age of 54 range: 38-71. The majority of pathogenic variants were observed in patients of European ancestry. The variant spectrum included known loss-of-function alleles, such as truncating and splice-site alterations, as well as selected missense changes with predicted deleterious impact, indicating a range of functional consequences relevant to tumor biology. Conclusions: In this large real-world BC cohort, CDH1 germline variants were observed in 11% of patients with variable prevalence by genetic ancestry. We identified 19 P/LP CDH1 variants in 23 BC patients. These germline variants remain strongly enriched in lobular BC histology, consistent with prior literature, with 0.25% of patients with lobular histology carrying variants classified as P/LP. The majority of P/LP variants localized to functionally important regions of the E-cadherin protein, including the extracellular and cytoplasmic domains, underscoring their likely disruption of cell-cell adhesion. These findings support broader consideration of CDH1 in germline testing panels for BC risk assessment. Overall, this study reinforces the clinical value of CDH1 germline analysis, particularly in lobular BC. Citation Format: B. Arun, S. Rivero-Hinojosa, R. Green, V. N. Aushev, A. Antonopolous, A. Rodriguez, M. C. Liu, J. E. Garber. Prevalence and Characterization of Germline CDH1 Mutations in a Large Real-World Breast Cancer Cohort abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-05.
Arun et al. (Tue,) studied this question.