In this cohort study of 284 Chinese patients with HDGC, the frequency of CDH1 germline alterations was low (2.8%), and germline alterations, insertions, and deletions were most frequently found in MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO. Double-hit events in genes such as CACNA1D were observed among patients with HDGC. This evidence concerns the gene RNF213 and Familial gastric cancer.