Medical Oncologist
CION Cancer Clinics
NTHL1, MSH3, AXIN2, GREM1 and RNF43: which cancers and what risk | CION Cancer Clinics
NTHL1, MSH3, AXIN2, GREM1 and RNF43 are rarer genes that cause polyps in the large bowel, and so raise the risk of bowel cancer. NTHL1 also raises the risk of some cancers outside the bowel. Nobody can yet give reliable risk figures, because few families have been studied. This page explains what each gene is linked with, and why regular colonoscopy matters more than any number. 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
- Which cancers do the rarer polyposis genes raise the risk of?
- What does each gene raise the risk of?
- How is your own risk worked out?
- The words you will meet, in plain language
- One faulty copy or two: what changes for NTHL1 and MSH3?
- What this page cannot tell you
- Four things families tell us about these genes
- Common questions about the rarer polyposis genes
The short answer
Which cancers do the rarer polyposis genes raise the risk of?
Mainly bowel cancer. NTHL1, MSH3, AXIN2, GREM1 and RNF43 each cause polyps to grow in the large bowel, and some of those polyps can turn into cancer if left in place. NTHL1 also raises the risk of several cancers outside the bowel. The exact size of each risk is not known, because only small numbers of families have been studied.
Why the numbers are so uncertain
These genes were linked to polyps relatively recently, and each one explains only a small share of families with many polyps. Risk figures from a handful of families can be far off the true value. Honest guidance says the risk is raised, higher than in the general population, and plans checks on that basis.
Why the risk can be brought down
Bowel cancer from polyps usually takes years to develop. Regular colonoscopy finds polyps and removes them before they change. That is why a result in one of these genes leads to a plan of checks, and why the numbers matter less than keeping to the plan.
A raised risk is not a diagnosis. Many carriers who keep to their checks never develop bowel cancer.Gene by gene
What does each gene raise the risk of?
The five genes behave differently. Two need a fault in both copies before risk rises. Three need only one.
NTHL1
Risk rises only when both copies are faulty, one from each parent. It causes bowel polyps and raises bowel cancer risk.
Also linked with
- Breast cancer in women
- Cancer of the womb lining
- Several other cancers, less clearly
MSH3
Also needs faults in both copies. It causes bowel polyps and a raised bowel cancer risk. Very few families have been described, so the full picture is still unclear.
AXIN2
One faulty copy is enough. It is linked with bowel polyps and bowel cancer, often alongside several missing adult teeth. The missing teeth can be the first clue in a family.
GREM1 and RNF43
One faulty copy is enough for each. GREM1 causes a mix of polyp types in the bowel. RNF43 is linked with serrated polyps, a type that can be flat and hard to spot. Both raise bowel cancer risk.
Not sure whether this applies to you?
Ask an oncologistHow doctors judge it
How is your own risk worked out?
The gene and the number of faulty copies
For NTHL1 and MSH3, a single faulty copy is treated very differently from two. For AXIN2, GREM1 and RNF43, one copy counts.
What colonoscopy has already found
The number, size and type of polyps removed so far says a great deal about how active the condition is in you.
Who in the family has had cancer
Bowel cancer at a young age in close relatives pushes the estimate up. A family with only polyps, and no cancers, pushes it down.
Other factors in your own life
Smoking, weight, diet and bowel inflammation all affect bowel cancer risk in everyone, carriers included. Some of these you can change.
On your report
The words you will meet, in plain language
- Polyposis
- Having many polyps in the bowel, far more than most people of the same age.
- Adenoma
- The most common kind of bowel polyp that can, over time, turn into cancer.
- Serrated polyp
- A polyp with a saw-tooth pattern under the microscope. Some types can turn into cancer and can be flat and easy to miss.
- Biallelic
- Both copies of a gene are faulty, one inherited from each parent. This is what NTHL1 and MSH3 need before risk rises.
- Monoallelic
- Only one copy is faulty. For NTHL1 and MSH3 this usually means a carrier with little or no extra risk.
- Penetrance
- How often a fault actually leads to disease across everyone who carries it. For these genes it is still being worked out.
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Side by side
One faulty copy or two: what changes for NTHL1 and MSH3?
Two faulty copies
One faulty copy
Bowel polyps and a raised cancer risk
Little or no extra risk has been shown
Regular colonoscopy is advised
Usually routine screening for age
Brothers and sisters may also be affected
Relatives can be told about carrier status
Each child will be a carrier, at least
A partner's test matters for children
Being straight with you
What this page cannot tell you
It cannot put a number on your own risk. For these genes, published figures come from small studies and differ widely. Any single percentage you find online is likely to be less reliable than it looks. Your counsellor and bowel specialist judge risk from your gene, your polyps and your family together.
It cannot read your report
Some laboratories report these genes only when asked, and some list changes in them as uncertain. A variant of uncertain significance is not a positive result. What your specific variant means is a question for the counsellor who ordered the test.
Who this does not apply to
Most people with a few polyps do not carry a fault in any of these genes. A single carrier of NTHL1 or MSH3, with no polyps and no family history, usually needs nothing beyond ordinary screening. Tumour testing that finds changes in RNF43 inside a cancer is a different matter, and it belongs with targeted therapy.
Studies so far are small. Expect advice on these genes to be updated as more families are described.Commonly believed
Four things families tell us about these genes
"A rare gene must mean a very high risk."
Rarity says how few families carry it, not how dangerous it is. For some of these genes the true risk may turn out lower than early reports suggested.
"I carry one NTHL1 fault, so I will get bowel cancer."
For NTHL1 and MSH3, one faulty copy has not been shown to raise risk much, if at all. Risk rises when both copies are faulty. Ask your counsellor which applies to you.
"If my colonoscopy is clear, I can stop having them."
A clear colonoscopy is reassuring for now. New polyps can grow over time, which is why checks continue at the gap your specialist sets.
"Missing teeth have nothing to do with cancer."
In families with an AXIN2 fault, several missing adult teeth can be the first sign. Mention missing teeth in the family when you meet a genetic counsellor.
Questions we are asked
Common questions about the rarer polyposis genes
How high is the bowel cancer risk with these genes?
Raised, and higher than in the general population, but nobody can give a reliable figure yet. Only small numbers of families have been studied for each gene. What is clear is that regular colonoscopy, with polyps removed, lowers the risk a great deal. That is where your effort is best spent.
Does NTHL1 raise the risk of breast cancer?
In women with two faulty copies, studies suggest a raised risk of breast cancer and of cancer of the womb lining. The evidence comes from small groups. Your counsellor can say whether extra breast checks are sensible for you, based on your result and your family history.
Are these genes the same as FAP or Lynch syndrome?
No. FAP comes from faults in APC, and Lynch syndrome from other repair genes. These five genes cause similar bowel problems, usually milder, and are tested when those better known causes have been ruled out or are included on the same panel.
Why was a gene on my report I have never heard of?
Modern panels test many bowel genes at once, including rare ones. A result in a rare gene can be genuinely useful, or can be an uncertain change with no clear meaning. Take the report to the counsellor who ordered it before acting on it.
Does a result change my cancer treatment?
It can shape surgery and follow-up if you already have bowel cancer, because more polyps may appear in the rest of the bowel. Your surgeon may weigh how much bowel to remove. The decision is made with your team and your full history, not from the gene alone.
Should my children be tested?
These genes raise risk in adult life, so children are usually not tested young. Testing is offered when checks would begin. For NTHL1 and MSH3, a child's risk depends on both parents, so the other parent's result matters too.
Does marrying within the family matter for these genes?
It can, for NTHL1 and MSH3. When both parents share an ancestor, they are more likely to carry the same fault, which is what a child needs to be affected. Mention it to your counsellor. It is a routine question, not a judgement.
Is colonoscopy for this covered by insurance or Aarogyasri?
Coverage for planned checks in someone without symptoms varies by policy and scheme. Ask your insurer in writing before the procedure, and ask the hospital billing desk what applies. Keep your genetic report with your claim, as it explains why the check was needed.
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
- National Cancer Institute — Genetics of Colorectal Cancer (PDQ) - Health Professional Version
- Gut (British Society of Gastroenterology) — Guidelines for the management of hereditary colorectal cancer from the BSG, ACPGBI and UKCGG
- MedlinePlus Genetics — AXIN2 gene
- National Cancer Institute — Genetic Testing for Inherited Cancer Susceptibility Syndromes
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
What the rarer polyposis genes doThe five genes explained, one at a timeSerrated polyposis syndrome and its geneticsWhere RNF43 fits, and why most cases have no gene foundTesting the family for the rarer polyposis genesWho else should be offered a testMUTYH carriers vs biallelic MUTYH-associated polyposisThe same one-copy or two-copy question, for a better known gene
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