Session # P-076

A novel missense variant in CDH1 causes hereditary diffuse gastric and lobular breast cancer syndrome independently of splicing

Take home points:  

1. CDH1 missense variant p.G212V (c.635G>T) implicated in hereditary diffuse gastric and lobular breast cancer syndrome (DGLBC). Notably, pathogenicity arises from the missense alteration, distinct from splicing disruption. 

2. Families carrying p.G212V met CDH1 testing criteria, exhibiting DGC and LBC histories. RNA analysis excluded splicing anomalies. Structural analysis highlighted destabilization potential, reinforced by similar p.G212E disease association. 

3. Despite clinical and structural evidence, p.G212V doesn't align with expert panel guidelines. Limited missense variant data inhibits classification. This case stresses the need for evolving guidelines as new pathogenic variants emerge. 

4. Pathogenic missense changes in CDH1 are rare and present unique challenges for variant interpretation. 

• Authors: Terra Brannan; Shabnam Asgari; Aida Akopyan; Matthew Varga; Ora Gordon; Marcy Richardson
• Collaborators: Providence Health
• Conference: CGA-IGC 2023
• Date: Thursday, Oct 26, 2023 8:00am - 1:30pm