PMS2 is a gene that produces a protein involved in repairing mistakes in a cell’s DNA. It is one of four key mismatch repair (MMR) proteins — along with MLH1, MSH2, and MSH6 — that work together to find and fix small errors that occur when DNA is copied during cell division. PMS2 and MLH1 work as a pair: MLH1 is required for PMS2 to function, so loss of MLH1 almost always results in loss of PMS2 as well.
If your pathology report mentions PMS2, it is likely because your tumour was tested to see whether this protein is present or absent. The result has important implications for understanding your diagnosis and, in some cases, whether you or your family members may be at increased risk for certain cancers.
What does it mean if PMS2 is “lost” in my tumour?
When a pathology report states that PMS2 expression is lost or absent, it means the tumour cells are not producing the PMS2 protein. Without this protein — or its partner MLH1 — the cell’s DNA repair system cannot function properly. This is called mismatch repair deficiency (dMMR). DNA errors that would normally be caught and corrected are allowed to accumulate, which can affect how the cancer behaves and how it may respond to treatment.
Because PMS2 depends on MLH1 to function, it is important to look at which proteins are lost together. There are two distinct patterns:
- Loss of both MLH1 and PMS2 — the most common pattern. This usually means that MLH1 has been lost first, and PMS2 has lost its partner. The cause may be sporadic (non-inherited) or Lynch syndrome. An additional test, MLH1 promoter methylation testing, is usually performed next to distinguish between these two possibilities.
- Loss of PMS2 alone (with MLH1 still present) — a less common but highly significant pattern. When PMS2 is lost without loss of MLH1, it is more likely to reflect a mutation in the PMS2 gene itself rather than a secondary consequence of MLH1 loss. Isolated PMS2 loss is a stronger indicator of Lynch syndrome, and germline genetic testing is typically recommended.
What does it mean if PMS2 is “retained” in my tumour?
When a pathology report states that PMS2 expression is retained or intact, it means the tumour cells are producing a normal amount of PMS2 protein. This is a normal result for this test. It means that loss of PMS2 is not contributing to the tumour’s development. The tumour’s mismatch repair status is determined by reviewing the results for all four MMR proteins together.
Why do pathologists test for PMS2?
PMS2 testing is performed as part of a four-protein MMR panel for two main reasons:
- To guide treatment. Tumours with loss of PMS2 (and therefore mismatch repair deficiency) often respond well to immunotherapy, specifically immune checkpoint inhibitors. Knowing the MMR status of a tumour helps your oncologist determine whether this type of treatment may be appropriate.
- To assess the risk of Lynch syndrome. Loss of PMS2, particularly when PMS2 is the only protein lost, is associated with an inherited condition called Lynch syndrome. Identifying this pattern helps determine whether you and your family members may benefit from genetic counselling and testing.
How is PMS2 tested?
Pathologists test for PMS2 using a laboratory technique called immunohistochemistry (IHC). A special antibody that binds to the PMS2 protein is applied to a thin slice of tumour tissue on a glass slide. If the protein is present, the cells change colour and are visible under the microscope. If the protein is absent, those cells remain unstained.
The pathologist compares staining in the tumour cells with that in surrounding normal cells (such as blood vessels and lymphocytes), which should stain normally and serve as an internal reference. A result is considered a true loss only when the tumour cells are unstained, and the surrounding normal cells retain intact staining.
PMS2 is always tested together with the other three MMR proteins — MLH1, MSH2, and MSH6 — as a panel. The specific combination of proteins that are lost is important for determining the next steps.
What causes loss of PMS2 in a tumour?
PMS2 can be lost in a tumour for two main reasons:
- Secondary loss of MLH1 is the most common cause. Because PMS2 depends on MLH1 to function and remain stable in the cell, loss of MLH1 almost always causes PMS2 to disappear as well. In this situation, PMS2 is not directly damaged — it simply has no partner. The underlying cause is the loss of MLH1, which may result from sporadic MLH1 promoter methylation or a germline mutation in MLH1 associated with Lynch syndrome.
- Direct mutation in the PMS2 gene. Less commonly, the PMS2 gene itself carries a mutation that prevents it from producing a functional protein. This mutation can be acquired (somatic) — occurring only in the tumour cells and not inherited — or inherited (germline), in which case it causes Lynch syndrome. Isolated PMS2 loss on IHC is the pattern most likely to reflect a direct PMS2 mutation.
What happens after PMS2 loss is identified?
The next steps after identifying PMS2 loss depend on the pattern seen on the MMR panel:
- If both MLH1 and PMS2 are lost, MLH1 promoter methylation testing is usually the next step. If methylation is found, the loss is most likely sporadic, and Lynch syndrome is less likely. If methylation is absent, germline genetic testing for Lynch syndrome is recommended.
- If PMS2 is lost in isolation, germline genetic testing is usually recommended directly, without methylation testing. Isolated PMS2 loss is a strong indicator of a PMS2 gene mutation, and Lynch syndrome should be considered.
Germline genetic testing is performed on a blood or saliva sample and looks for an inherited mutation in the PMS2 (or other MMR) gene. This testing is typically arranged through a genetic counsellor or medical genetics service.
What will my pathology report say?
PMS2 is always included in a four-protein MMR panel alongside MLH1, MSH2, and MSH6. The result for each protein will be described using one of the following terms:
- Retained (or intact) — the protein is present in the tumour cells. This is a normal result for this test.
- Lost (or absent, or loss of expression) — the protein is missing from the tumour cells. This is an abnormal result.
The overall MMR result will then be summarized as one of the following:
- MMR-proficient (pMMR) — all four proteins are retained. The DNA repair system is intact.
- MMR-deficient (dMMR) — one or more proteins are lost. The report will specify which proteins are absent — for example, “loss of MLH1 and PMS2” or “loss of PMS2 only.”
The specific pattern of protein loss is important because it guides the next steps. The two most common patterns involving PMS2 are:
- Loss of both MLH1 and PMS2 — the most common pattern in dMMR colorectal and endometrial cancers. Because PMS2 depends on MLH1 to function, loss of MLH1 almost always brings PMS2 down with it. MLH1 promoter methylation testing is usually performed next to determine whether the cause is sporadic or hereditary.
- Loss of PMS2 alone is a less common but significant pattern. When PMS2 is the only protein lost, it is more likely to reflect a direct mutation in the PMS2 gene. This pattern is a stronger indicator of Lynch syndrome, and germline genetic testing is typically recommended.
Questions to ask your doctor
- My report shows loss of PMS2 — which other proteins were lost or retained?
- Based on this pattern, what are the next steps — methylation testing or genetic testing?
- Does this result affect whether I am eligible for immunotherapy?
- Should I be referred for genetic counselling or testing for Lynch syndrome?
- Should my family members be informed or offered genetic testing?