Session # 597F

Beyond the NMD Boundary: Characterizing the Phenotypes of C-terminal CDH1 Mutations

  • C-terminal truncating alterations in CDH1 escape the nonsense-mediated mRNA pathway. It’s possible that these truncated proteins retain partial function, and variants in this region must be interpreted with caution.
  • Using clinical data, molecular evidence, and structural information, we characterized truncating alterations in the CDH1 gene that were identified downstream of the NMD boundary in a large diagnostic laboratory cohort of ~400,000 alleles.
  • We reported three pathogenic C-terminal truncations in families meeting International Gastric Cancer Linkage Consortium (IGCLC) diagnostic criteria. Additionally, we identified the most C-terminal pathogenic mutation in our cohort, which occurred de novo in an individual with lobular breast cancer. Identifying the most C-terminal mutation allows us to classify other, upstream C-terminal truncating alterations as pathogenic or likely pathogenic.

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