Clinical Domain Working Groups

Pathogenic germline variants in CDH1 have been associated with hereditary diffuse gastric cancer (HDGC, MIM# 137215), an autosomal dominant cancer predisposition syndrome. Heterozygous CDH1 carriers of pathogenic variants have a significantly increased risk of developing diffuse gastric cancer (DGC). In addition to gastric cancer, female heterozygous carriers are at risk of developing lobular carcinoma of the breast. Identification of CDH1 carriers is important, because the characteristic microscopic foci of signet ring cell adenocarcinoma in HDGC usually involves the submucosa and is often not readily detectable by routine upper endoscopy screening (Fitzgerald et al., 2010). Due to the aggressive nature of DGC, the clinical management recommendation for risk reduction is prophylactic gastrectomy. Given the quality of life issues as a consequence of this preventative and irreversible surgery, it is imperative that patients and their providers be given high quality information while trying to limit uncertainty. This Expert Panel will provide assessment regarding the pathogenicity of variants in CDH1 with respect to a HDGC phenotype.