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Why PMS2 is harder to test than other genes | CION Cancer Clinics
PMS2 is hard to test because part of it has a near-identical copy nearby in your DNA, called a pseudogene. Standard sequencing can mistake one for the other, which can raise a false alarm or miss a real fault. Careful laboratories use extra checks to tell them apart. This page explains why it happens, what your report might say, and what to ask. At CION Cancer Clinics, our oncologists explain what a gene result means for you and your family, and plan the checks that follow.
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Medically reviewed by Dr. Naresh GunduConsultant Medical Oncologist · MBBS, DNB (Internal Medicine), DM (Medical Oncology, AIIMS) · last reviewed September 2026, next review due September 2027
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On this page
- Why is PMS2 harder to test than other genes?
- What can the pseudogene do to a result?
- How does a careful laboratory handle PMS2?
- What do the testing words mean?
- What might a PMS2 report say, and what does it mean?
- What do people wrongly assume about PMS2 tests?
- What can this page not tell you?
- Common questions about PMS2 testing
The short answer
Why is PMS2 harder to test than other genes?
Because your DNA holds a near-identical copy of the back end of the PMS2 gene. This copy is called a pseudogene, and its name is PMS2CL. It sits close to PMS2 on the same chromosome and does no useful work. Standard tests read DNA in short pieces, and a short piece of PMS2 can look exactly like a piece of its copy.
What a pseudogene is
A pseudogene is an old, broken duplicate of a real gene. It stopped working long ago, but its spelling is still almost the same. Most genes tested for cancer risk do not have one. PMS2 does, and that single fact explains most of the difficulty.
Why the two keep swapping spelling
The gene and its copy sometimes exchange stretches of DNA, a process called gene conversion. So even the few letters that normally tell them apart can move between them. A laboratory cannot rely on those letters alone to decide which one it is reading.
The difficulty is technical, not medical. It does not make a PMS2 fault more dangerous.Where it goes wrong
What can the pseudogene do to a result?
There are four ways the copy can mislead a test. A careful laboratory guards against each one.
A false alarm
A change that really sits in the harmless copy can be reported as if it were in PMS2. The person is then told they may have Lynch syndrome when they do not.
A missed fault
A real fault in PMS2 can stay hidden because the test cannot place it, or because the region was left out. Some older panels did not fully cover the affected part of the gene.
A negative result is only as good as the part of the gene the test could read.A deletion that cannot be placed
Missing chunks of DNA are a common kind of PMS2 fault. Standard deletion tests can see that something is missing, but not always which copy lost it.
An unclear report
Some reports say the laboratory could not tell whether a change is in PMS2 or its copy. That is an honest answer, not a result.
What it needs next
- A second, confirming method
- Tumour stain results, if available
- A counsellor to explain the plan
Not sure whether this applies to you?
Ask an oncologistChecking a result properly
How does a careful laboratory handle PMS2?
Screen with a standard gene panel
Most testing starts with a panel that reads many genes at once. It is fast and covers most of PMS2 well, but it cannot settle the back end of the gene on its own.
Flag anything in the shared region
Any change found where PMS2 and its copy look alike is marked for a second look. It is not reported straight away as a positive result.
Confirm with a longer read
A method called long-range PCR copies one long stretch of DNA that starts in a part only PMS2 has. Anything found inside that stretch must belong to the real gene, not the copy.
Report only what is confirmed
The final report should say clearly whether a change is in PMS2. If it cannot be placed, the report should say so rather than guess.
On your report
What do the testing words mean?
- Pseudogene
- A non-working copy of a gene with almost the same spelling. For PMS2, the one that matters is called PMS2CL.
- Gene conversion
- Stretches of DNA swapping between a gene and its copy. It blurs the letters that normally tell them apart.
- Next-generation sequencing (NGS)
- The standard method that reads DNA in many short pieces at once. Fast, but short pieces cannot always be placed.
- Long-range PCR
- A way of copying one long stretch of DNA, starting where only PMS2 exists, so the gene is read without its copy.
- MLPA
- A test that looks for missing or extra chunks of a gene. For PMS2 it needs careful interpretation.
- Variant of uncertain significance (VUS)
- A change the laboratory cannot yet call harmful or harmless. It should not change your care.
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Reading the report
What might a PMS2 report say, and what does it mean?
The report says
What it usually means
Pathogenic variant in PMS2, confirmed
An inherited fault is present. Counselling and a care plan follow.
Variant found, gene or pseudogene not resolved
Not a diagnosis yet. More testing is needed.
No pathogenic variant found
Ask whether the whole gene was covered
Variant of uncertain significance
Do not act on it. Wait for reclassification.
Deletion found, origin unclear
A follow-up test should place it
Commonly believed
What do people wrongly assume about PMS2 tests?
"A negative PMS2 result from any laboratory rules it out."
It depends on the method. If the test could not read the back end of the gene well, a real fault may have been missed. Ask the counsellor whether the whole gene was covered.
"If the report shows a PMS2 change, I have Lynch syndrome."
Only if the change is confirmed in the real gene and classed as harmful. In one recent study, many apparent faults flagged in the shared region were not confirmed when checked with long-range PCR.
"Any gene panel is just as good for PMS2."
Panels differ in how they handle the pseudogene, and the price does not tell you which approach was used. A reliable laboratory should explain how it confirms changes in the shared region.
"The difficulty means PMS2 results cannot be trusted."
A confirmed result is reliable. The difficulty lies in reaching confirmation, which takes extra steps and sometimes extra time. Once that is done, the answer is as firm as for any other gene.
Being straight with you
What can this page not tell you?
It cannot tell you whether your own test was done well or whether a flagged change is real. That depends on the laboratory's method, which is usually described in the small print of the report. What your specific variant means is a question for the counsellor who ordered the test.
When a second look is worth asking for
If a family history strongly suggests Lynch syndrome and a tumour stain showed PMS2 was missing, a negative blood result deserves a second conversation. Your counsellor can check whether the test fully covered the gene and whether another method is needed.
Who this does not apply to
Most people reading this do not need to worry about pseudogenes. If you have not been tested, or your testing was for a different gene, none of this affects you. Tumour tests to choose a cancer drug answer a different question, covered under targeted therapy.
Questions we are asked
Common questions about PMS2 testing
What is PMS2CL?
It is the pseudogene, a non-working copy of the back end of PMS2 that sits nearby on the same chromosome. It has no job in the cell. It matters only because it looks so much like PMS2 that tests can confuse the two.
Can the pseudogene itself cause cancer?
No. It is not an active gene, and changes in it are not known to raise cancer risk. The only problem is that a change in the copy can be mistaken for a change in the real gene, which is why confirmation matters.
Why do some PMS2 reports take longer?
When a change turns up in the shared region, the laboratory runs a second, more careful method to confirm where it sits. That extra step adds time. It is a sign of good practice, not a problem with your sample.
Should I repeat an old PMS2 test?
Sometimes. If your test was done some time ago and your family history or a tumour stain points to PMS2, ask your counsellor whether the method covered the whole gene. Repeating a test without answering that question first rarely helps.
Does a tumour stain help?
Yes. If a relative's tumour stain showed PMS2 missing on its own, that steers the blood test towards PMS2 and tells the laboratory where to look harder. It also gives the counsellor good reason to question a negative blood result rather than close the matter early.
Will the same problem affect my relatives' tests?
Less so. Once a fault is confirmed in one family member, relatives are tested for that exact change, usually with the confirming method from the start. That makes family testing more direct than the first test in the family.
Does PMS2 testing cost more?
It can, when confirmation is needed, because an extra method is run. Ask the laboratory before testing whether confirmation is included in the price you are quoted, so there is no surprise later.
Where do I start if my report says unresolved?
Take the report to the counsellor who ordered the test and ask what follow-up is planned. Bring any tumour stain results from relatives. Call the CION helpline if you are not sure who to approach, and someone will point you to the right clinic.
Your Specialists
Meet CION's oncologists. Bring your family history or genetic report to them.
Our medical oncologists see people with a strong family history of cancer, arrange genetic counselling and testing where it fits, and plan the checks that follow.
Medical Oncologist
Dr. C. Raghavendra Reddy
MBBS(Gold Medal), DNB(General Medicine), DM(Medical Oncology)(Gold Medal)
Medical Oncologist
Dr. Bharati Devi Gorantla
MBBS, MD(General Medicine), DM(Medical Oncology)(Adyar,Chennai), ECMO, MRCP SCE(UK)
Medical Oncologist
Dr. Owais Mohammed
MBBS, MD (General Medicine), DrNB (Medical Oncology), ECMO, MRCP SCE (Medical Oncology) (UK)
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Sources
- GeneReviews (NCBI) — Lynch Syndrome
- MedlinePlus Genetics — PMS2 gene
- Human Mutation — Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes
- Frontiers in Oncology — Evaluation of pathogenic variants detected in high homology regions of the PMS2 gene. How effective is long-range PCR?
This page is general information, not a prescription. Do not change or stop any treatment based on what you read here. If anything is worrying you, contact your own treating team — or call our helpline and we will help you reach the right specialist.
Keep reading
Related pages
The PMS2 gene: what it does and why it mattersWhat the gene is for, before the testing problemHow next-generation sequencing worksThe standard method, and where it strugglesPMS2 mutation: which cancers and what riskWhat a confirmed result actually raisesTesting the family for PMS2How relatives are tested once a fault is confirmed
Talk to us
Does your PMS2 report say the result is unresolved?
Tell us what the report says and whether a relative's tumour was stained. We will help you reach a counsellor who can plan the follow-up. One helpline serves every CION centre.