Hereditary diffuse gastric cancer (HDGC) is a cancer predisposition syndrome with significantly elevated life-time risks of gastric and breast cancer due to loss-of-function (LOF) germline variants of the CDH1 gene. There is considerable variability across affected families in its clinical manifestations including age-of-onset and cancer phenotype.

In this study, we identified associations between location of CDH1 mutation and frequencies of clinical phenotypes. Families with truncating variants located in the PRE-PRO-region of the CDH1 gene were six times more likely affected by colorectal cancer, variants in the intracellular region were protective for cancer at young age and in the linker regions for breast cancer. These genotype-phenotype associations may aid identification of high-risk groups and individualize risk-reducing intervention strategies pending future validation and creation of risk prediction models. (By Dr. Udo Rudloff, https://jmg.bmj.com/content/early/2019/02/11/jmedgenet-2018-105361 )