When mismatch repair immunohistochemistry shows combined loss of MLH1 and PMS2, the commonest cause in colorectal and endometrial cancer is sporadic MLH1 promoter hypermethylation, not Lynch syndrome. Testing for MLH1 promoter methylation, or BRAF V600E in colorectal cancer, separates the two before a patient is referred for germline testing.
Isolated loss of MSH2, MSH6 or PMS2, or MLH1 loss without methylation, points more strongly to a germline cause and should go straight to genetics referral.
- Report which MMR proteins are lost, not just 'deficient'.
- For MLH1 and PMS2 loss, recommend MLH1 promoter methylation testing, or BRAF V600E in colorectal cancer.
- Recommend genetics referral for loss of MSH2, MSH6 or isolated PMS2, and for unmethylated MLH1 loss.
- Check internal positive controls before calling loss.
Why it matters
The pattern of loss decides whether a family needs genetic counselling.
Read the rest in the app
You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.
Scan to keep reading on your phone. No account needed to start.
Tomorrow morning, before your first patient
One edition a day for pathology, written by the desk, every claim tied to its paper. Six minutes.
Get the app — free