Background:Familial aggregation occurs in approximately 10% of cases of gastric cancer. The genetic predisposition or cause of the disease in only about 40% of hereditary gastric cancer cases is known, while the genetic factors of the remaining cases remain to be studied.Methods:Samples were collected from a family with gastric cancer, including 3 gastric cancer and 17 healthy samples. Whole-exome sequencing was performed on samples from 3 patients with gastric cancer and 1 sample from healthy peripheral blood.SAMD9Lwas knocked down using small interfering RNAs and short hairpin RNA. The expression ofSAMD9Lwas detected by quantitative real-time polymerase chain reaction and Western blot in SGC-7901 cells. CCK-8 assay was used to detect the proliferation of gastric cancer cells. The migration and invasion of gastric cancer cells were detected by Transwell assay and scratch assay. The cell apoptosis was detected by flow cytometry.Results:Twelve single-nucleotide variants and 9 insertions/deletions mutation sites were identified as candidate genes. Among them,SAMD9Lregulates cell proliferation as a tumor suppressor gene. The experiments of knocking downSAMD9Lin SGC-7901 cells revealed that reduced expression ofSAMD9Lsignificantly enhanced the proliferation, migration, and invasion of SGC-7901 cells.Conclusions:These results suggest thatSAMD9Linhibits the proliferation of gastric cancer cells, thereby increasing the risk of gastric cancer in people withSAMD9Ldownregulation. Therefore,SAMD9Lmay represent a susceptibility gene of this gastric cancer family.