{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPMS2 is an essential component of the DNA mismatch repair (MMR) system, functioning primarily as the MLH1 binding partner in the heterodimeric MutLα complex that corrects replication errors and maintains genomic stability. Numerous studies have underscored the clinical utility of analyzing PMS2 expression by immunohistochemistry as a surrogate marker for MMR deficiency in tumors such as endometrial and colorectal cancers, which in turn facilitates the identification of Lynch syndrome. In addition to its diagnostic value, investigations have revealed that germline mutations and loss of expression of PMS2, while sometimes confounded by technical challenges posed by pseudogenes, contribute to a distinct spectrum of cancer predisposition with variable penetrance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the functional level, PMS2 participates in multiple aspects of the DNA damage response. Its interaction with partner proteins extends beyond MLH1 to include associations with factors such as FANCJ, and it is implicated in modulating apoptosis through interactions with p73, thereby enhancing DNA damage–induced cell death. Moreover, biochemical and structural studies have demonstrated that the MutLα complex (via its PMS2 subunit) requires ATP binding and hydrolysis for conformational transitions critical to its repair function. Additional work has established that PMS2 is necessary for proper immunoglobulin class switch recombination by facilitating generation of double‐strand DNA breaks, and that defects in PMS2 activity—whether due to missense mutations, gene conversion events, or complete loss—result in diminished repair capacity and atypical tumor spectra, including features in breast and glioblastoma contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, PMS2 mutations display a unique profile characterized by a relatively low penetrance compared with other MMR gene defects, yet they significantly contribute to hereditary cancer syndromes as well as to sporadic tumor behavior in several organs (including colorectal, ovarian, prostate, and even pediatric brain tumors). Advances in mutation detection have refined the identification of PMS2 alterations despite the complications from pseudogene interference. These findings emphasize not only the critical role of PMS2 in preserving genomic integrity but also its broader impact on tumor biology, risk stratification, and therapeutic surveillance in affected individuals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Heather Hampel, Wendy Frankel, Jenny Panescu, et al. 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