BACKGROUND Immunohistochemical (IHC) staining for mismatch repair (MMR) proteins is useful for gastric cancer treatment and prognosis. Different IHC staining patterns reflect the complex biological phenomena underlying MMR deficiency. We herein report a rare IHC staining pattern of four MMR-related proteins in gastric cancer. CASE SUMMARY A "null" IHC staining pattern of four MMR-related proteins, including MLH1, PMS2, MSH2, and MSH6, in a 67-year-old male patient with gastric cancer pT3N3aM0 revealed promoter hypermethylation of MLH1. Next-generation sequencing showed that these four genes exhibited changes. One of these was the somatic mutation of the missing copy number in exon 14 of MSH2. Mutation analysis using peripheral blood showed no germline mutations in these four genes. The patient had no history of personal or family tumor history. We classified this case as sporadic. The patient returned to normal after operation, and there were no signs of tumor metastasis and recurrence. After six cycles of adjuvant chemotherapy, the patient was discharged in a stable condition. The patient had a mild reaction to chemotherapy and a good prognosis. At present, 16 mo after the operation, the patient's condition is stable. CONCLUSION Abnormal MMR protein expression, helpful for individualized follow-up care, helped identify a sporadic case lacking familial clinical management implications.