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.
Authors: Kate Krempely; Carin Espenschied; Ira Lu; Adam Chamberlin; Rachid Karam