S4101 Navigating Uncertainty: A Case of Colonic Polyposis and a PMS2 Variant of Uncertain Significance in Suspected Lynch Syndrome

Introduction: Lynch syndrome is an autosomal dominant inherited germline mutation in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2. It increases risk significantly for colon cancer and other malignancies. In patients presenting with early-onset of malignancy, ≥10 cumulative adenomatous polyps, or a family history fulfilling Amsterdam II criteria, identification of pathogenic MMR variants is essential for guiding screening and management of both patients and at-risk relatives. Genetic testing may reveal mutation variants of these genes with uncertain significance (VUS) complicating clinical decision-making. Case Description/Methods: A 77-year-old man with no known family history of colorectal cancer underwent a screening colonoscopy in 2020 showing a 2.5 cm tubulovillous adenoma requiring piecemeal resection and a 2 mm tubular adenoma. A colonoscopy in 2021 showed a 4 mm tubulovillous adenoma and 2 tubular adenomas less than 1 cm. Colonoscopy in 2024 showed a 4 cm tubular adenoma requiring piecemeal EMR and 7 additional tubular adenomas less than 1 cm. His polyp history prompted genetic testing. This revealed a mutation on chromosome 7 involving a PMS2 c.*3G >A VUS located in the 3′ untranslated region. This mutation is listed in ClinVar in association with Lynch syndrome, however it remains uncharacterized in the literature. Discussion: This case highlights the management challenges posed by a VUS in a gene classically associated with Lynch syndrome. VUS findings, such as PMS2 c.*3G >A, lack sufficient evidence for definitive risk stratification for colon cancer as opposed to pathogenic MMR variants which enable tailored surveillance. This specific non-coding variant may affect post-transcriptional regulation which would explain this patient’s polyp burden, however oncogenic potential remains unclear. Most PMS2-associated Lynch syndrome cases follow autosomal dominant inheritance, however biallelic mutations may result in constitutional mismatch repair deficiency (CMMRD), a rare autosomal recessive disorder. Alternatively, some non-inherited cases may result from 2 somatic mutations, known as double somatic hits. Surveillance decisions in patients with VUS mutations should be based on clinical history. Given the accelerated adenoma-to-carcinoma sequence associated with PMS2 mutations (1–2 years vs 7–10 years in sporadic cases), annual colonoscopic surveillance was recommended for this patient. Family members should also be informed and offered genetic counseling.