MLH1 – Lynch syndrome

MLH1 is a core DNA mismatch repair (MMR) gene whose heterozygous germline mutations cause Lynch syndrome, an autosomal dominant predisposition to colorectal and extracolonic cancers. Loss of MLH1 function leads to microsatellite instability (MSI) and high tumor mutational burden (PMID:19133695). The consistent observation of MLH1 defects across diverse populations underlines its critical role in genome maintenance.

Autosomal dominant inheritance of MLH1 variants has been documented in >200 unrelated probands, with segregation in >50 multigeneration families (PMID:23112559; PMID:26185136). Case reports include somatic mosaicism in sibships (PMID:19133695) and de novo frameshift events (c.1771delG) in simplex cases (PMID:23112559). Co-segregation of pathogenic alleles with colorectal and endometrial cancers further supports high penetrance.

The MLH1 variant spectrum encompasses truncating (nonsense, frameshift), splice-site, and missense changes. Recurrent alleles include the American founder splice donor mutation c.589-2A>G (PMID:21671475). Functional classification studies have confirmed pathogenicity of truncating mutations and implicated specific missense changes (e.g., p.Arg659Pro) in MMR deficiency. Example variant: c.1050del (p.Gly351AlafsTer) identified in multiple tissues with MSI-H phenotype (PMID:19133695).

Biochemical assays demonstrate that MLH1 ATPase activity and PMS2 heterodimerization are essential for MMR. Mutant MLH1 proteins bearing N-terminal ATPase site alterations abrogate repair in vitro (PMID:11897781). Carboxy-terminal domain deletions disrupt MLH1–PMS2 complex formation and MMR activity (PMID:11793442). Mouse models deficient for full-length Brca1 and Mlh1 further underscore the role of MLH1 in meiotic recombination and genome stability.

Some MLH1 missense variants outside consensus domains may retain MMR function and show low penetrance (PMID:15354210). Such discordance highlights the need for combined genetic, segregation, and functional assessment for variant interpretation.

Integration of robust genetic segregation, extensive variant catalog, and orthogonal functional assays classifies MLH1–Lynch syndrome as a definitive gene–disease relationship. MLH1 testing guides diagnostic confirmation, risk stratification, and informs cascade screening for Lynch syndrome families.

References

• American journal of medical genetics. Part A • 2009 • Somatic mosaicism in a patient with Lynch syndrome. PMID:19133695
• World journal of gastroenterology • 2012 • A de novo germline MLH1 mutation in a Lynch syndrome patient with discordant immunohistochemical and molecular biology test results. PMID:23112559
• Japanese journal of clinical oncology • 2015 • A novel deletion in the splice donor site of MLH1 exon 6 in a Japanese colon cancer patient with Lynch syndrome. PMID:26185136
• International journal of cancer • 2012 • An American founder mutation in MLH1. PMID:21671475
• Journal of biological chemistry • 2002 • Contribution of human mlh1 and pms2 ATPase activities to DNA mismatch repair. PMID:11897781
• Genes, chromosomes & cancer • 2002 • Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. PMID:11793442
• British journal of cancer • 2004 • MSH6 missense mutations are often associated with no or low cancer susceptibility. PMID:15354210

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