# MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)

Source: https://onco.cc/terms/mlh1-promoter-methylation/  
OnCo record `mlh1-promoter-methylation` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When a tumour has lost the MLH1 mismatch-repair protein, a methylation test on the tumour tells the two causes apart: methylation switching the gene off means a sporadic cancer, no methylation means an inherited Lynch syndrome mutation is likely and the whole family needs testing.

## Summary

What is measured: whether the MLH1 gene has been silenced by promoter methylation rather than by an inherited mutation. How: after mismatch repair immunohistochemistry shows loss of MLH1 (with PMS2), the tumour is tested by methylation-specific PCR or pyrosequencing of the MLH1 promoter; in colorectal cancer BRAF V600E sequencing serves the same purpose because it is present in about 70 percent of sporadic methylated tumours and virtually never in Lynch syndrome (it is not useful in endometrial cancer). About three-quarters of MLH1-deficient colorectal cancers and 70 to 90 percent of MLH1-deficient endometrial cancers are methylated and sporadic; the rest go to germline testing of MLH1, MSH2, MSH6, PMS2 and EPCAM, with the rare constitutional MLH1 epimutation in mind. What a result changes: a methylated result closes the germline question, though the tumour remains mismatch repair-deficient and eligible for pembrolizumab, nivolumab or dostarlimab, and a BRAF-mutant microsatellite-unstable colorectal cancer carries a worse prognosis; an unmethylated result triggers genetic counselling, cascade testing, colonoscopy surveillance for relatives, aspirin chemoprevention (CAPP2) and consideration of risk-reducing hysterectomy in Lynch syndrome. Where it matters: MSI-high colorectal cancer, mismatch repair-deficient endometrial cancer and MSI-high gastric cancer.

## Fields

- Kind: Term
- Last checked: 2026-09-17
- Also known as: MLH1 promoter hypermethylation; MLH1 hypermethylation; MLH1 methylation; sporadic MSI-high; sporadic dMMR; epigenetic MLH1 silencing; MLH1 silencing; BRAF V600E reflex testing; reflex testing for Lynch syndrome

## Connected records

- terms: [BRAF V600E mutation](https://onco.cc/terms/braf-v600-mutation/), [Hereditary cancer syndromes](https://onco.cc/terms/hereditary-cancer-syndromes/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/)
- technologies: [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [MSI and mismatch-repair testing](https://onco.cc/technologies/msi-mmr-testing/)
- drugs: [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- cancers: [Endometrial cancer with no specific molecular profile](https://onco.cc/cancers/endometrial-nsmp/), [Microsatellite-unstable (MSI-high) gastric cancer](https://onco.cc/cancers/gastric-msi-high/), [Mismatch-repair deficient (MSI-high) colorectal cancer](https://onco.cc/cancers/msi-high-colorectal/), [Mismatch-repair-deficient endometrial cancer](https://onco.cc/cancers/endometrial-mmr-deficient/)

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