Universal mismatch-repair (MMR) testing on colorectal and endometrial cancers catches Lynch syndrome, informs prognosis and flags likely immunotherapy responders. It is cheap, but the interpretation step is where errors creep in.
Stain for the four proteins as two pairs, MLH1 with PMS2 and MSH2 with MSH6, and read loss by pairs: PMS2 loss with MLH1 loss, MSH6 loss with MSH2 loss. Isolated loss of PMS2 or MSH6 is still abnormal. The common trap is calling MLH1/PMS2 loss Lynch syndrome without the reflex step.
When MLH1 and PMS2 are both lost, reflex to BRAF V600E or MLH1 promoter methylation: a positive result points to sporadic hypermethylation, while a negative result keeps Lynch syndrome in play and should prompt germline referral. Document the pattern and the reflex result so the clinical team can act on it.
- Run MMR immunohistochemistry (MLH1, PMS2, MSH2, MSH6) on all colorectal and endometrial cancers.
- Read loss by pairs, and treat isolated PMS2 or MSH6 loss as abnormal.
- On combined MLH1/PMS2 loss, reflex to BRAF V600E or MLH1 promoter methylation.
- A negative reflex keeps Lynch syndrome in play and warrants germline referral.
Why it matters
The reflex step is what separates sporadic hypermethylation from inherited Lynch syndrome, and skipping it both over-calls Lynch and misdirects families.
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