Lynch Syndrome Genetic Testing
When you have been diagnosed with colon cancer, endometrial cancer or another cancer and it is suspected that you may have Lynch syndrome, or when a family member has been diagnosed with Lynch syndrome and you have undergone genetic counseling to better understand the risks, benefits and limitations of genetic testing
A blood sample drawn from a vein, a sample of saliva collected in a clean container, or a swab from the inside of your cheek (buccal swab)
Lynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited condition that can increase your risk of developing colon cancer, endometrial (uterine) cancer, and several other cancers. It is associated with harmful (pathogenic or likely pathogenic) variants of mismatch repair genes. Lynch syndrome genetic testing evaluates multiple genes associated with Lynch syndrome for such variants.
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DNA errors can occur when DNA is copied as cells grow and divide. Normally, DNA errors are fixed by the mismatch repair system. With Lynch syndrome, there is a change in one of the repair genes that prevents the mismatch repair system from working properly. The system is not able to fix DNA errors, which then start to accumulate within the cell. Eventually, the cells with these accumulated DNA errors can begin to grow and divide uncontrollably, which may lead to cancer.
Lynch syndrome genetic tests are blood tests that identify the specific mismatch repair gene variants that are associated with the disorder. If you are diagnosed with colon cancer, endometrial cancer, or another cancer suspicious for Lynch syndrome, this testing can determine whether a pathogenic variant in a mismatch repair gene is the likely cause.
If you have genetic testing done because a family member has been tested for Lynch syndrome and a pathogenic variant was identified, then the results can tell you if you have inherited the same gene variant. Not everyone with a gene variant associated with Lynch syndrome will develop cancer, but if you have a pathogenic variant, you have an increased risk of cancer over your lifetime compared to the general population. You may benefit from working with your healthcare practitioner to increase the frequency of your cancer screenings like colonoscopies.
The mismatch repair genes associated with Lynch syndrome that may be tested include:
There are a few different ways that the genetic variants may be tested. The approach that is used depends upon what is already known.
- Multi-gene panel testing – this approach uses DNA sequencing to evaluate MLH1, MSH2, MSH6, PMS2, and EPCAM genes all at the same time for pathogenic variants. This panel may be ordered if your healthcare provider suspects Lynch syndrome but it is not clear which of the mismatch repair genes may be affected, so all of them are tested. This approach is commonly used when a familial pathogenic variant has not already been identified in your family. Sometimes, genes associated with other syndromes that increase your risk for developing cancer may be included on a panel and tested at the same time, since there are other less common conditions that are similar to Lynch syndrome.
- Single gene sequencing with deletion/duplication analysis – this type of testing evaluates the DNA sequence of a single mismatch repair gene and looks for pathogenic variants either in the sequence itself or caused by missing or extra sections of DNA. This test may be ordered if a sample of your tumor has already been tested and a deficiency in a certain mismatch repair gene is suspected.
- Targeted testing – this method tests a single mismatch repair gene when someone in your family has been diagnosed with Lynch syndrome and the gene variant has already been identified. It only looks for the specific variant found in your family member(s).
How is the test used?
Lynch syndrome genetic testing is used to help determine if you have inherited a harmful gene variant (pathogenic or likely pathogenic variant) in one of the mismatch repair genes associated with Lynch syndrome. This may be done to:
- Help diagnose Lynch syndrome and identify the specific gene variant that is the probable cause
- Determine if you have a gene variant that has already been identified in one of your family members who has Lynch syndrome; if you have a pathogenic variant, you have an increased risk of developing colon cancer, endometrial cancer or another cancer.
When is it ordered?
This testing may be ordered when you have been diagnosed with colon cancer, endometrial cancer or another cancer and your healthcare practitioner suspects that you have Lynch syndrome, especially if:
- You are relatively young (e.g., younger than age 50)
- Results of your tumor testing suggests Lynch syndrome (See the Common Question on tumor testing below.)
- Your cancer has returned after treatment
- You have a close family member or multiple extended family members diagnosed with cancers associated with Lynch syndrome
For more details, see the Common Question below on who should have genetic testing for Lynch syndrome.
What does the test result mean?
If you have been diagnosed with cancer and genetic testing identifies a pathogenic variant of one of the mismatch repair genes, then you have Lynch syndrome and the variant identified is likely associated with your cancer.
If you have been identified as having the same gene variant as a family member with Lynch syndrome, then you will have an increased lifetime risk of cancer and a 50% chance of passing this variant on to your children. People who have a pathogenic variant in MLH1 or MSH2 tend to have a greater number of Lynch syndrome-related cancers than those with other gene variants.
If you have a pathogenic variant, you do have an increased risk of Lynch-syndrome related cancers, but it doesn't mean you will definitely develop cancer. Some people with a pathogenic variant in a Lynch syndrome gene never develop cancer.
If testing does not identify a pathogenic gene variant associated with Lynch syndrome, then it is likely that you do not have the inherited condition. If you have been tested for a known familial pathogenic variant that caused Lynch syndrome in a relative and you test negative for that variant, your risk for Lynch syndrome-related cancer is likely significantly reduced. However, just like any test, a negative result does not completely rule out the possibility that you have Lynch syndrome. Your healthcare provider or genetic counselor will help you interpret the meaning of your test result.
Who should have genetic testing for Lynch syndrome?
The decision about who should be tested is usually based on specific criteria. Your healthcare practitioner may talk to you about the Amsterdam II criteria and/or the revised Bethesda guidelines. These guidelines were developed as screening tools to help determine your likelihood of having Lynch syndrome and whether you should consider being tested for Lynch syndrome. The criteria and guidelines look at colorectal cancer and endometrial cancer in your family history and personal history. According to these guidelines, you should consider further testing for Lynch syndrome in the following circumstances:
Amsterdam II Criteria—testing is recommended if you fit all these criteria:
- Three or more relatives with Lynch syndrome-associated cancer, one of whom is a first-degree relative (e.g., mother, father, sibling) of the other two
- Cancer involving at least two generations in your family
- One or more of the related cancers diagnosed in a relative before 50 years of age
Revised Bethesda Guidelines—testing is recommended if you fit any one of these criteria:
- Diagnosis of colorectal cancer or endometrial cancer when you are younger than 50 years of age
- More than one colon cancer at the same time (synchronous), additional cancers at another time (metachronous), or other Lynch syndrome-associated tumors, regardless of how old you are
- Diagnosis of colorectal cancer with a high frequency of microsatellite instability when you are younger than 60 years of age
- Diagnosis of colorectal cancer in one or more first-degree relatives (parents, siblings, children) with a Lynch syndrome-related tumor, with one of the diagnoses before 50 years of age
- Diagnosis of colorectal cancer in two or more first- or second-degree (uncles, aunts, nieces, nephews or grandparents) relatives with Lynch syndrome-related cancers, at any age
Even if you don't fit these criteria, you may still consider genetic testing if you have had a Lynch syndrome-related cancer and results of your tumor tests suggest an increased likelihood of Lynch syndrome.
I was diagnosed with colon cancer and testing was first done on my tumor. Why?
When a tumor sample (biopsy) is available, testing is often first done to evaluate for a mismatch repair deficiency, microsatellite instability and MLH1 promoter methylation. These tumor tests can help screen patients to identify which patients should then consider genetic testing for Lynch syndrome gene variants, which can sometimes indicate the probable gene involved. (See the Testing section in the article on Lynch Syndrome for more information on tumor testing.)
How long will it take for Lynch syndrome genetic test results?
What other cancers are associated with Lynch syndrome?
Colon cancer and endometrial cancer are the most common cancers associated with Lynch syndrome, but others include cancer of the bile ducts, brain, kidneys, liver, ovaries, pancreas, skin, small bowel, stomach, and urinary tract. For more information, see the article on Lynch Syndrome or the links in the Related Content section.
Are there other reasons for mismatch repair deficiency or microsatellite instability?
Yes. Mismatch repair deficiency and/or microsatellite instability is the cause of many colon cancers and endometrial cancers. For example, estimates are that about 12% to 14% of all cases of colorectal cancer have a mismatch repair deficiency. In most cases of colorectal cancer with mismatch repair system problems (70% to 90%), there are acquired (not inherited) genetic changes that cause accidental inactivation or shutdown of the system (promoter methylation of the MLH1 gene). These cases are known as sporadic cancer, or cancer that develops on its own without inherited changes in the mismatch repair genes. These are not related to Lynch syndrome.
Additional tumor testing, such as for BRAF mutation and MLH1 promoter methylation, may be performed to help distinguish between Lynch syndrome-related cancer and non-inherited (sporadic) cancer. (See the article on Lynch Syndrome for more on these tumor tests.)
If I have a Lynch syndrome pathogenic gene variant, how is my cancer risk monitored?
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Why is this condition primarily called Lynch syndrome, not Hereditary non-polyposis colorectal cancer (HNPCC)?
It is known by both names, but Lynch syndrome is now the preferred term. The syndrome is named after Dr. Henry Lynch, who first identified and described the condition.
HNPCC has lost favor as the name because it implies that:
- The affected person will not have colon polyps – but in fact, individuals with Lynch syndrome often do have colon polyps.
- It is only related to colon cancer – but the condition is also related to a number of other cancers.
How do you know a mismatch repair gene variant is harmful (pathogenic)?
Laboratory directors and genetics professionals rely on databases and medical literature in order to interpret and correctly classify the results of these tests. Some variants identified by Lynch syndrome testing are already known to be pathogenic, or disease causing, because they have been seen in many other people with Lynch syndrome. Others are predicted to be disease-causing because of their effect on the gene or protein.
A variant may also be considered "likely pathogenic" if there is sufficient supporting evidence that it would act in the same manner as a known pathogenic variant. Some gene variants may be identified as "variants of uncertain significance" (VUS). A VUS means that the variant has not been reported to be causative of a condition, but that it is also not a frequent variant in the general population (which would support it being a common and benign, or non-disease causing variant). This means that they are not the gene variants that are known to cause Lynch syndrome, but it is not yet known if they should be considered pathogenic.
As knowledge in these areas continues to grow and more information becomes available, the interpretation of "variants of uncertain significance" is sometimes downgraded (likely benign or benign) or upgraded (likely pathogenic or pathogenic). Due to the evolving nature of variant interpretation, if your result is classified as a VUS, it is important to work with your healthcare provider to monitor its classification over time.