Genomic coordinate (human 14:75,013,775 MLH3) & (mouse 12:85,281,294 Mlh3).
Cytoband (human 14q24.3 MLH3) & (mouse 12qD1 Mlh3).
Here I present: “Endometrial Carcinoma”, Victor McKusick, Mendelian Inheritance in Man’, 1966. (MLH3) icd10=C54.1
Approximately 20% of endometrial carcinoma demonstrate microsatellite instability (MSI), a reflection of mutations in mismatch repair genes. The mismatch repair genes that have been identified as having a role in endometrial cancer include MSH2, MSH3, MSH6, MLH1, and MLH3.
Endometrial Carcinoma & MLH3.
Context.
Endometrial carcinoma (EC), especially the endometrioid subtype, is frequently linked to defects in DNA mismatch repair (MMR), leading to microsatellite instability (MSI).
The core MMR genes clinically relevant in EC are MLH1, MSH2, MSH6, and PMS2.
Where MLH3 fits
MLH3 (MutL homolog 3) is an MMR-related protein that forms a heterodimer with MLH1 (MutLγ).
Its role is minor and auxiliary compared with MLH1/PMS2 (MutLα), which perform the bulk of post-replicative MMR.
Evidence in endometrial carcinoma
Pathogenic MLH3 mutations are rare in EC.
MLH3 alterations alone do not usually produce classic MSI-high tumors.
MLH3 is not considered a Lynch syndrome gene in current clinical criteria.
Some studies report variants of uncertain significance (VUS) or low-penetrance polymorphisms, but:
No consistent association with EC risk
No validated prognostic or predictive value
Clinical Practice.
Routine testing for MLH3 is not recommended in EC.
Standard workup includes:
IHC for MLH1, MSH2, MSH6, PMS2
If MLH1 loss → MLH1 promoter methylation testing
Treatment decisions (e.g., PD-1 inhibitors) depend on MMR deficiency/MSI-H, not MLH3 status.
Bottom Line.
MLH3 is biologically interesting but clinically peripheral in endometrial carcinoma.
EC MMR pathology is driven overwhelmingly by MLH1/PMS2 or MSH2/MSH6 loss, not MLH3.
There evidence tha endometrial carcinoma is caused by mutation in the MutL homolog-3 (MLH3) encoded on genomic coordinate 14:75,013,775 and cytoband 14q24.3 in humans.
