Lynch syndrome associated with the pathogenic MSH2 p.A230Lfs*16 variant presenting with sequential colorectal, endometrial, and ampullary cancers: a case report

Background Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer, is one of the most prevalent hereditary tumor syndromes. Its primary pathogenic mechanism lies in germline mutations of DNA mismatch repair (MMR) genes, which trigger genomic instability and substantially elevate the risk of malignant transformation in multiple organs. The hallmark clinical manifestations of LS include early-onset malignancies, multiple synchronous or metachronous primary neoplasms, distinct familial hereditary predisposition, as well as characteristic molecular phenotypes of tumors such as high microsatellite instability (MSI-H) and loss of MMR protein expression. Case summary The patient was diagnosed with moderately differentiated transverse colon adenocarcinoma with mucinous components in June 2015. In December 2015, endometrial malignant transformation arising from endometrial polyps was confirmed. The patient developed hypertension around 2021, with blood pressure controlled by oral amlodipine besylate. Cerebral thrombosis was identified in 2023, followed by symptomatic supportive treatment. In May 2026, ampullary carcinoma was newly diagnosed. Germline genetic testing revealed a frameshift variant MSH2 p.A230Lfs * 16, confirming the diagnosis of LS. According to the patient’s self-report, her nephew was also diagnosed with LS via genetic testing, but this diagnosis could not be independently verified. Conclusion This case documents an unusual clinical course of three sequential primary malignancies in a carrier of the known pathogenic MSH2 p.A230Lfs * 16 germline variant. For patients with multiple primary neoplasms and a positive family history of malignant tumors, early LS screening is recommended. Lifelong comprehensive tumor surveillance should be conducted among LS patients to enable early diagnosis and prompt treatment, ultimately prolonging patient survival. Core tip We report a rare Lynch syndrome patient carrying a known pathogenic germline MSH2 p.A230Lfs * 16 variant complicated with sequential colorectal, endometrial and ampullary carcinoma. The patient received radical surgeries and adjuvant chemotherapy, with dual immunotherapy planned for ampullary cancer. According to the patient’s self-report, her nephew was also diagnosed with LS, but this diagnosis has not been independently verified. This case provides an additional phenotypic observation of this known pathogenic frameshift variant, and it should be noted that a single case report cannot establish or expand the variant-specific tumor susceptibility spectrum. This report emphasizes the importance of early LS screening and lifelong surveillance for individuals with multiple primary malignancies.