Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM)

Lynch syndrome is an inherited condition that raises the lifetime risk of several cancers, most importantly cancer of the colon and rectum and cancer of the uterus. It is caused by a change in one of five genes: MLH1, MSH2, MSH6, PMS2, and EPCAM. It was once called hereditary nonpolyposis colorectal cancer, or HNPCC, and older reports and family records may still use that name.

Lynch syndrome is the most common hereditary cancer syndrome, affecting roughly 1 in 300 people. Most carriers do not know they have it. It accounts for about 2% to 4% of all colorectal cancers and a similar share of uterine cancers.

Two key points shape this condition’s understanding. First, the risk varies greatly depending on which of the five genes is affected. These genes were once considered part of one syndrome with uniform risks; now, they are known to act quite differently, and a carrier’s specific gene largely determines the appropriate surveillance and its timing. Second, Lynch syndrome is among the most manageable hereditary cancers, as its primary cancers can often be detected early or prevented entirely through regular screenings.

This article is written both for people who have been diagnosed with a cancer linked to Lynch syndrome and for people who carry a gene change without having had cancer, often identified after a relative was tested. If you are in the second group, most of what follows is about prevention rather than treatment.

What do the mismatch repair genes do?

Every time a cell divides, it copies about three billion letters of DNA, and it makes mistakes. Mismatch repair is the system that finds and corrects those copying errors, a kind of spell-check that runs behind every cell division.

Four proteins do most of this work, and they operate in pairs: MLH1 works with PMS2, and MSH2 works with MSH6. Because they work in pairs, losing one partner often destabilizes the other, which is why a report may describe two proteins as lost together. The fifth gene, EPCAM, does not make a repair protein at all; it sits immediately next to MSH2, and certain deletions in EPCAM switch off the neighboring MSH2 gene, producing the same effect.

These are tumor suppressor genes. Everyone carries two copies of each. A person with Lynch syndrome is born with one working copy and one that does not work. That single working copy is enough for normal life, but if it is damaged in any individual cell over a lifetime, that cell loses its ability to correct copying errors. Mistakes then accumulate rapidly, and a cell that would ordinarily take decades to become cancerous can do so far faster. This is why the cancers in Lynch syndrome appear earlier than usual, and why a polyp in the colon can progress to cancer over two or three years rather than the ten or more typical of the general population. That accelerated timeline is the reason colonoscopy is repeated so often in this condition.

Cancers associated with Lynch syndrome

Lynch syndrome raises the risk of a defined group of cancers. The figures below are cumulative risks to about age 75, given as ranges across published studies, with the general population risk alongside for comparison. Risks differ substantially by gene, and where that difference is large it is given by gene.

Colorectal cancer

Cancer of the colon and rectum is the cancer most associated with Lynch syndrome. Lifetime risk is roughly 40% to 60% for MLH1 and MSH2 carriers, roughly 10% to 25% for MSH6, and roughly 10% to 20% for PMS2, compared with about 4% in the general population. The average age at diagnosis is in the forties for MLH1 and MSH2 carriers, roughly ten to fifteen years earlier than sporadic colorectal cancer, and later for MSH6 and PMS2.

These cancers arise more often on the right side of the colon than sporadic ones, and they arise from adenomas that progress unusually quickly. Under the microscope, they often show abundant immune cells within and around the tumor, and pathologists recognize this appearance as a prompt to test for mismatch repair loss. People who have had one colorectal cancer face a substantial risk of a second, separate cancer elsewhere in the colon later, which is the main reason surgery for colorectal cancer in Lynch syndrome is discussed differently than it is for other people.

Endometrial cancer (cancer of the uterus)

For women, cancer of the endometrium, the lining of the uterus, is as important as colorectal cancer and for some genes more so. Lifetime risk is roughly 30% to 45% for MLH1, 40% to 55% for MSH2, 40% to 45% for MSH6, and 13% to 25% for PMS2, compared with about 3% in the general population.

The MSH6 pattern is different again. Women carrying an MSH6 change have a high risk of endometrial cancer alongside only a modestly raised risk of colorectal cancer, which means MSH6 families can go unrecognized as having Lynch syndrome because the colon cancers that would prompt suspicion never appear. For many women, endometrial cancer is the first Lynch-related cancer to occur, arriving years before any colorectal cancer would.

Ovarian cancer

Lifetime risk of ovarian cancer is roughly 10% to 20% for MLH1, MSH2, and MSH6 carriers, compared with about 1% in the general population. PMS2 carriers appear to be at little or no increased risk, and current guidance notes they may reasonably decline preventive removal of the ovaries. The average age at diagnosis is around 45, considerably younger than sporadic ovarian cancer.

Stomach and small bowel cancer

Lifetime risk of stomach cancer is roughly 5% to 10%, highest in MLH1 and MSH2 carriers, compared with under 1% in the general population. Cancer of the small bowel carries a similar order of risk and is otherwise a rare cancer. Because Helicobacter pylori infection compounds stomach cancer risk, testing for and treating it is generally offered to carriers.

Urinary tract cancer

Cancer of the lining of the renal pelvis, ureter, and bladder occurs in roughly 2% to 15% of carriers, with MSH2 carriers at the high end of that range and at particular risk in later decades. This is one of the clearest gene-specific differences in the syndrome.

Other cancers

Lynch syndrome also raises the risk, to a smaller degree, of cancers of the pancreas and bile ducts, the brain, and the prostate, with MSH2 carriers again at the higher end for brain and prostate. Certain skin tumors arising from oil-producing glands, called sebaceous adenomas and sebaceous carcinomas, are characteristic enough that their appearance sometimes leads to the diagnosis; this combination is known as the Muir-Torre variant of Lynch syndrome.

Lynch syndrome is not associated with a meaningfully increased risk of most common cancers, including lung cancer, and the evidence for a link with breast cancer remains weak and is not currently a basis for extra breast screening.

How lifetime risk is estimated and why the numbers vary

Published risk figures for Lynch syndrome vary widely. There are two reasons for this, and knowing them makes the numbers easier to interpret.

The earliest estimates came from families identified precisely because many members had cancer, often across several generations. Studies of such families overstate risk for the average carrier, because the families were selected for having a lot of cancer in the first place. As genetic testing became routine and carriers began to be found in families with unremarkable histories, the estimates fell.

The second and larger source of variation is the gene itself. When all five genes were treated as one syndrome, published risks were averages across a mixed group. The large prospective studies that followed thousands of carriers over time showed that the genes behave very differently. Taking overall cancer risk to age 75 as a single measure, MLH1 and MSH2 carriers face roughly a 70% to 85% chance of developing some cancer, MSH6 carriers roughly 40% to 60%, and PMS2 carriers roughly 35%. For context, the lifetime risk of developing some cancer in the general population is around 40%. A PMS2 carrier reading the older literature would find figures that simply do not describe their situation.

Three further points affect an individual’s estimate:

Family history — A carrier with several close relatives affected at young ages faces a higher risk than a carrier found incidentally in a family with no history.
Sex — Risks differ substantially for men and women, and not only because of the gynecologic cancers.
Whether surveillance is in place — Published lifetime risks generally describe what happens without regular colonoscopy. Effective surveillance changes the picture considerably.

Finally, a high lifetime risk is not a certainty. Even in the highest-risk group, a meaningful proportion of carriers never develop cancer. Both halves of that are true, and a genetics service can give an estimate that reflects your gene, your sex, and your own family.

Who should be tested?

Most people with Lynch syndrome are now identified in one of two ways.

The first is testing of the tumor itself. Nearly all colorectal and endometrial cancers are now tested for mismatch repair loss at the time of diagnosis, regardless of the person’s age or family history. This universal approach replaced the older practice of testing only people who met family history criteria, which missed a large share of cases. If your cancer report mentions MMR immunohistochemistry or microsatellite instability, this is that test.

The second is family history. Germline testing is generally offered when a person has colorectal or endometrial cancer diagnosed under about 50, when someone has had more than one Lynch-related cancer, when several relatives on the same side of the family have had Lynch-related cancers, or when a known gene change has already been identified in the family.

Older criteria known as the Amsterdam and Bethesda guidelines are still occasionally referenced. They were designed to select families for testing on history alone, and they miss a substantial number of carriers. A family that does not meet them has not been ruled out.

How the test is performed

Two different tests are involved, and they answer different questions.

Tumor testing is performed by the pathologist on tissue already removed at biopsy or surgery, and requires nothing further from the patient. Immunohistochemistry uses antibodies to show whether each of the four repair proteins is present in the tumor cells. A separate molecular method tests for microsatellite instability, a pattern of errors in repetitive stretches of DNA that appears when repair has failed. Either test can be used, and many laboratories perform both.

Tumor testing identifies repair failure but does not distinguish inherited from acquired causes. When MLH1 is the protein lost, an additional step follows: testing for MLH1 promoter methylation, and sometimes for a BRAF V600E mutation. Both point toward a non-inherited cause, which explains the large majority of MLH1 loss, particularly in older people. This step spares many people unnecessary genetic testing.

Germline testing is performed on a blood or saliva sample and examines the DNA a person was born with. It is done by next generation sequencing together with a method that detects large deletions, since some Lynch-causing changes, particularly in EPCAM, are deletions that sequencing alone can miss. This is the test that diagnoses Lynch syndrome, and it is usually done as part of a panel covering many hereditary cancer genes at once.

How results are reported

Germline results are reported in categories describing how confident the laboratory is that a change affects the gene:

Pathogenic or likely pathogenic variant — A change known, or strongly expected, to stop the gene working. This is a positive result and confirms Lynch syndrome. The report will name the gene, which determines the surveillance plan.
Variant of uncertain significance — A change was found, but there is not enough evidence to say whether it affects the gene. This is not a positive result and is not a basis for preventive surgery. It is managed as though the result were negative, with surveillance guided by family history. Most such variants are eventually reclassified as harmless as evidence accumulates, which is why staying in contact with the genetics service matters.
Benign or likely benign variant — A harmless difference in the gene. Everyone carries many of these.
No variant identified — No change was found in the genes tested. What this means depends on the family, as explained below.

What the result means

A pathogenic or likely pathogenic variant confirms Lynch syndrome. The gene named on the report determines which cancers are of greatest concern, when surveillance begins, and how often it is repeated. Each of the person’s children, siblings, and parents has a 50% chance of carrying the same change.

A negative result means two quite different things depending on the situation, and confusing them is consequential:

True negative — A specific variant has already been identified in the family and you tested negative for that exact variant. You did not inherit it, your risk returns to that of the general population, and your children cannot inherit it from you. Routine screening applies.
Uninformative negative — No variant has been identified in anyone in the family. This rules out the genes tested but does not rule out an inherited cause. Surveillance continues based on family history rather than on the test result.

A third situation arises when a tumor shows mismatch repair loss, methylation testing does not explain it, and germline testing finds nothing. This is called Lynch-like syndrome. Most such cases turn out to be caused by two acquired changes within the tumor itself rather than an inherited condition, but because that cannot always be confirmed, families are usually offered surveillance similar to Lynch syndrome until the picture is clearer.

Germline versus somatic mismatch repair changes

This distinction causes more confusion than any other aspect of Lynch syndrome, and the stakes of getting it wrong are high in both directions.

A germline change is present in the DNA a person was born with, exists in every cell of the body, and can be passed to children. This is Lynch syndrome.

A somatic change arises within a tumor during a person’s lifetime. It exists only in the cancer cells, cannot be inherited by children, and carries no implications for relatives.

Most mismatch repair loss found on tumor testing is not inherited. Around 15% of colorectal cancers show repair failure, and the large majority of those are caused by MLH1 promoter methylation, an acquired change that accumulates with age. Only a minority represent Lynch syndrome. A tumor report describing loss of a repair protein, or an MSI-high result, is therefore a reason to investigate further, not a diagnosis of an inherited condition.

The reverse error also occurs. A comprehensive tumor sequencing panel that reports a mutation in a mismatch repair gene is testing the tumor, not inherited DNA, and cannot by itself establish Lynch syndrome. If such a result has been reported and nobody has discussed germline testing with you, you can ask whether it would be appropriate.

Surveillance and risk reduction

Lynch syndrome is among the most manageable hereditary cancer conditions, because its two principal cancers can be caught early or prevented. What the care team considers depends on the gene involved, sex, age, and whether childbearing is complete.

Colonoscopy

Regular colonoscopy is the single most effective measure available, and unusually among cancer screening tests, it does not merely detect cancer but prevents it, because polyps are removed during the examination before they can become cancerous.

For MLH1, MSH2, and EPCAM carriers, colonoscopy is generally recommended every one to two years starting at age 20 to 25, or two to five years before the earliest colorectal cancer in the family if that occurred before 25. For MSH6 and PMS2 carriers, where risk is lower and cancers occur later, it generally starts at age 30 to 35 on the same interval. The short interval reflects how quickly polyps progress in this condition rather than any expectation that something will be found each time.

Gynecologic cancer

No screening test for endometrial cancer has been shown to reduce deaths, so the primary strategy is different from the colon. It rests on recognizing symptoms early: abnormal bleeding between periods, unusually heavy bleeding, or any bleeding after menopause, each of which warrants prompt evaluation with a sample of the uterine lining. Endometrial cancer usually announces itself with bleeding at an early and curable stage, which is why this approach works reasonably well. Some centers additionally offer annual endometrial sampling and ultrasound from around age 30 to 35, though the evidence supporting it is limited.

Removal of the uterus and ovaries after childbearing is complete is the definitive option and is generally discussed around age 40 to 45, though timing is individual. It eliminates the risk of endometrial and ovarian cancer, and it brings surgical menopause if the ovaries are removed before natural menopause, with its own consequences for bone health, cardiovascular health, and quality of life that are weighed alongside the cancer risk. For PMS2 carriers, whose ovarian risk appears close to the general population, declining removal of the ovaries is considered a reasonable choice.

Aspirin

Daily aspirin has been shown in a randomized trial to reduce colorectal cancer risk in Lynch syndrome by roughly a third over ten years of follow-up. Guidelines now suggest carriers consider it. The optimal dose is still being established, and because aspirin carries a risk of bleeding, whether and at what dose to take it is a decision made with the care team rather than a blanket recommendation.

Other surveillance

Upper endoscopy — Generally offered every two to four years from age 30 to 40 for MLH1, MSH2, and MSH6 carriers, examining the stomach and upper small bowel. Testing for and treating H. pylori is offered at the same time.
Urine testing — Annual urinalysis from age 30 to 35 is offered in many centers, particularly for MSH2 carriers, though the evidence supporting it is limited.
Skin examination — Every one to two years for MLH1, MSH2, and MSH6 carriers, looking for the characteristic sebaceous tumors. These risks have not been established for PMS2.
Prostate — Men are generally offered a discussion about PSA screening from around age 40.

If cancer is diagnosed

Two aspects of treatment differ for people with Lynch syndrome. When colorectal cancer is found, the surgical discussion includes whether to remove a larger portion of the colon than the tumor alone would require, because the risk of a second, separate colorectal cancer later is substantial. A more extensive operation reduces that risk but has a greater effect on bowel function, and the balance differs with age and with the gene involved.

Second, cancers with mismatch repair loss respond unusually well to immunotherapy. Drugs including pembrolizumab and dostarlimab are approved for dMMR or MSI-high cancers regardless of where the cancer started, and response rates in this group are among the highest seen in solid tumors. This is covered in more detail in our article on mismatch repair and microsatellite instability across cancer types.

Cancers arising in Lynch syndrome tend to have a better outlook than their sporadic counterparts at the same stage. Ten-year survival after colorectal, endometrial, or ovarian cancer in carriers exceeds 80% in large prospective studies.

Testing family members

Lynch syndrome is inherited in an autosomal dominant pattern, meaning a single altered copy of the gene is enough to cause it. Each child, sibling, and parent of a carrier has a 50% chance of carrying the same change. It affects men and women equally and can be inherited from either parent. Families sometimes assume that a condition causing uterine and ovarian cancer must come from the mother’s side, and that assumption leads whole branches of families to conclude wrongly that they are not at risk.

Once a specific variant is identified in one family member, relatives can be tested for that exact change. This is called cascade testing, and it is simpler, cheaper, and far more definitive than the original test, because the laboratory knows exactly what to look for and the answer is a clear yes or no.

Testing is usually offered to adult relatives, and commonly from around age 18 to 20, since surveillance for the classical form of Lynch syndrome does not begin before then. Genetics services routinely help with the practical work of notifying relatives, including providing a letter that can be passed on.

There is one rare situation in which the answer changes completely. When a child inherits a non-working copy of the same mismatch repair gene from both parents, the result is a distinct and far more severe condition called constitutional mismatch repair deficiency, which causes cancers in childhood along with café-au-lait skin patches, and which requires surveillance beginning in early childhood. This is uncommon and generally arises where both parents carry a change in the same gene.

What happens next

What follows a Lynch syndrome diagnosis depends on the situation in which it was found.

For someone newly diagnosed with a Lynch-related cancer, cancer treatment proceeds; the germline result does not delay it. What it adds is a possible change to the surgical plan, eligibility for immunotherapy, a surveillance plan for the other organs at risk, and referral for family testing.

For a carrier who has not had cancer, the work is entirely preventive: establishing a colonoscopy schedule appropriate to the gene, discussing gynecologic risk reduction and its timing where relevant, considering aspirin, arranging the other surveillance appropriate to the gene, and arranging cascade testing for relatives.

Care is usually coordinated by a hereditary cancer clinic or genetics service, often working with gastroenterology and, for women, gynecology. Because surveillance continues for decades and the schedule differs by gene, having one team hold the plan matters more here than in most conditions. Support is also available for the practical questions that follow a diagnosis, including how to talk to relatives, and, in some countries, questions about insurance and employment.

Questions to ask your doctor

Which gene is involved in my case, and how does that change my risks compared with the other Lynch syndrome genes?
Was my result a pathogenic variant, or a variant of uncertain significance?
Was the testing able to detect large deletions as well as sequence changes?
Based on my gene, my sex, and my family history, what are my estimated lifetime risks?
At what age should my colonoscopies start, and how often should I have them?
Which other examinations do I need, and at what age do they begin?
Should I consider taking daily aspirin, and at what dose?
If I am a woman, what are the options for reducing my risk of uterine and ovarian cancer, and when should I consider them?
What symptoms should prompt me to contact you between scheduled examinations?
Which of my relatives should be offered testing, and can you provide a letter for them?
At what age should my children be tested?
If my tumor showed mismatch repair loss but no inherited change was found, what does that mean for me and my family?
If I need surgery for colorectal cancer, should a larger portion of the colon be removed?
Am I eligible for immunotherapy, and is there a clinical trial I should know about?