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MLH1, a core DNA mismatch repair (MMR) gene, is implicated in Lynch syndrome (LS), an autosomal dominant disorder predisposing to colorectal, endometrial, and ovarian cancers. Germline MLH1 pathogenic variants impair post-replicative MMR, leading to microsatellite instability (MSI) and loss of MLH1 protein expression in tumors. Carriers exhibit an ~19-fold increased risk of ovarian cancer compared with the general population (PMID:22331944).
Inheritance of MLH1 pathogenic variants follows an autosomal dominant pattern with incomplete penetrance. Pathogenic variants co-segregate with disease in multiple LS families, although formal segregation counts in ovarian cancer kindreds are limited. Deep sequencing has excluded somatic mosaicism in cases where metachronous colon and ovarian tumors harbored identical MLH1 truncating variants, confirming a clonal origin of metastasis rather than a second primary (PMID:29124495).
Case series have identified MLH1 loss in ovarian tumors: three of 128 unselected ovarian cancers showed MLH1 exon deletions or point mutations in patients suggestive of HNPCC (PMID:16360201), and two of 98 early-onset cases (T (p.Gln542Ter) in a patient with synchronous ovarian and colon tumors, both showing MLH1 loss (PMID:29124495).
Population-based studies have further characterized MLH1 variant spectrum in ovarian cancer. A common promoter polymorphism (c.-93G>A) conferred a modest but significant increased risk (OR = 1.5) in 899 cases versus 931 controls (PMID:18405947). Systematic reviews report that ~10% of unselected ovarian cancers exhibit MSI or MLH1 loss, indicating a substantial subset with MMR deficiency (PMID:21140452).
Functional assays have demonstrated that MLH1 truncating and splice-site mutations abrogate MMR activity. In vitro transcription-translation and yeast complementation assays confirmed loss of MLH1 function for variants such as c.2142G>A (p.Trp714Ter) and splice acceptor mutations (PMID:8880570). MLH1 ATPase activity is required for repair, with pathogenic variants showing conformational defects and impaired mismatch processing (PMID:11897781). Concordant immunohistochemistry and MSI data in ovarian tumors support a haploinsufficiency mechanism.
Some common MLH1 variants (e.g., c.-93G>A) exert low penetrance and are associated with modest risk, illustrating phenotypic variability and the need to distinguish pathogenic truncating mutations from risk alleles. No high-penetrance refuting evidence for MLH1-ovarian cancer association has been reported.
Collectively, genetic and functional evidence from multiple independent cohorts supports a Strong clinical validity for MLH1 in ovarian cancer. Genetic evidence is Strong based on at least 25 ovarian cancer patients with MLH1 pathogenic variants across five studies, and functional evidence is Moderate with concordant MMR deficiency assays. MLH1 testing has clear diagnostic utility in women with early-onset or familial ovarian cancer, guiding LS screening and risk-reducing interventions. Key Take-home: Germline MLH1 truncating variants confer autosomal dominant predisposition to ovarian cancer via mismatch repair deficiency, with actionable implications for surveillance and management.
Gene–Disease AssociationStrongPathogenic MLH1 variants in ovarian cancer across multiple cohorts with MSI-high tumors and loss of expression Genetic EvidenceStrong≥25 ovarian cancer patients with germline MLH1 pathogenic variants across five independent studies Functional EvidenceModerateConsistent in vitro and cellular assays demonstrating loss of mismatch repair function for MLH1 truncating and splice-site variants |