Disease characteristics. Lynch syndrome, caused by a germline mutation (i.e. pathogenic variant in the germline) in a mismatch repair gene and associated with tumors exhibiting microsatellite instability (MSI), is characterized by an increased risk for colon cancer and cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following life time risks for cancer are seen: 52%-82% for colorectal cancer (mean age at diagnosis 44-61 years); 25%-60% for endometrial cancer in women (mean age at diagnosis 48-62 years); 6% to 13% for gastric cancer (mean age at diagnosis 56 years); and 4%-12% for ovarian cancer (mean age at diagnosis 42.5 years; approximately 30% are diagnosed before age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.
Diagnosis/testing. The diagnosis of Lynch syndrome can be made on the basis of family history in those families meeting the Amsterdam criteria who have tumor microsatellite instability (MSI) or on the basis of molecular genetic testing in an individual or family with a germline mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). MLH1 and MSH2 germline mutations account for approximately 90% of pathogenic variants in families with Lynch syndrome; MSH6 pathogenic variants in about 7%-10%; and PMS2 pathogenic variants in fewer than 5%. Germline deletions in EPCAM (not a mismatch repair gene) inactivate MSH2 in about 1% of individuals with Lynch syndrome.
Genetic testing for Lynch syndrome is ideally performed in a stepwise manner:
Evaluation of tumor tissue for MSI through molecular MSI testing and/or immunohistochemistry (IHC) of the four MMR proteins. The presence of MSI in the tumor alone is not sufficient to diagnosis Lynch syndrome because 10%-15% of sporadic colorectal cancers exhibit MSI. IHC testing helps identify the MMR gene that most likely harbors a germline mutation.
Molecular genetic testing of the tumor for MLH1 methylation and somatic BRAF mutation to help identify those tumors more likely to be sporadic than hereditary.
Molecular genetic testing of the MMR genes to identify a germline mutation when findings are consistent with Lynch syndrome.
Management. Treatment of manifestations: For colon cancer, full colectomy with ileorectal anastomosis is recommended.
Prevention of primary manifestations: Prophylactic removal of the colon prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because routine colonoscopy is an effective preventive measure. Prophylactic removal of the uterus and ovaries (prior to the development of cancer) can be considered after childbearing is completed.
Surveillance: Colonoscopy with removal of precancerous polyps every one to two years beginning between ages 20 and 25 years or two to five years before the earliest age of diagnosis in the family, whichever is earlier. The efficacy of surveillance for cancer of the endometrium, ovary, stomach, duodenum, and urinary tract is unknown.
Agents/circumstances to avoid: Cigarette smoking.
Evaluation of relatives at risk: Genetic testing for Lynch syndrome is generally not recommended for at-risk individuals younger than age 18 years; however, because it is recommended that screening begin ten years before the earliest age of cancer onset in a family, molecular genetic testing and screening colonoscopy may need to begin before age 18 years in some families.
Genetic counseling. Lynch syndrome is inherited in an autosomal dominant manner. The majority of individuals diagnosed with Lynch syndrome have inherited the condition from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction as a result of screening or prophylactic surgery, or early death, not all individuals with a pathogenic variant in one of the genes associated with Lynch syndrome have a parent who had cancer. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known. Requests for prenatal testing for typically adult-onset conditions which (like Lynch syndrome) have treatment available are not common.
The diagnosis of Lynch syndrome can be made on the basis of family history in those families meeting the Amsterdam criteria who have tumor microsatellite instability (MSI) or on the basis molecular genetic testing in an individual or family with a germline mutation (i.e. pathogenic variant in the germline) in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or in EPCAM.
In 1990 the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer established the first clinical criteria, the Amsterdam criteria, to define hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) for the purpose of identifying families for research studies. These criteria were later modified (Amsterdam II Criteria) to include the other Lynch syndrome-related cancers (Table 1).
Although the Amsterdam criteria can be a significant predictor of a germline mutation in an MMR gene in families that fulfill the criteria, the Amsterdam criteria nonetheless fail to identify a large portion of persons with a germline MMR gene mutation. Therefore, family history and the Amsterdam criteria cannot be relied on to identify all individuals with a germline mutation in one of the MMR genes.
- Sjursen et al  found the sensitivity of the Amsterdam II criteria to be 87%, 62%, 38%, and 48% for identifying persons with a MLH1, MSH2, PMS2, or MSH6 germline mutation, respectively.
- Hampel et al  also reported that in a population-based study of persons with colon cancer, only three of 23 persons with a germline mutation in an MMR gene met the Amsterdam criteria.
Note: An individual found to have a deleterious germline mutation in one of the four MMR genes associated with Lynch syndrome is considered to have Lynch syndrome regardless of the extent of the family history.
Microsatellite instability (MSI) and/or immunohistochemistry (IHC) tests can be performed on tumor tissue in order to:
- Establish the probability of Lynch syndrome;
- Identify which gene is most likely to have a causative germline mutation in a person with Lynch syndrome.
Plausible etiologies to explain the results of tumor testing and recommended additional testing based on the results of tumor testing are summarized in Table 2.
- Although testing of tissue from colorectal carcinoma is clearly preferable, testing can be considered on an adenomatous polyp if cancer tissue is not available. However, abnormal MSI or IHC may be less reliably identified in Lynch syndrome-related polyps. Evaluation of 109 polyps from 69 individuals with a pathogenic variant found that only 79% of the adenomas demonstrated loss of MMR expression. Polyps with high-grade dysplasia are more likely to be concordant with pathogenic variant status than polyps with low-grade dysplasia [Walsh et al 2012].
- Testing can also be used to screen endometrial cancers for defective MMR [Backes et al 2009].
Immunohistochemistry (IHC) of tumor tissue. IHC detects the presence or absence of the protein products expressed by mismatch repair genes. The MMR gene products function as dimers: MSH2 protein may complex with MSH6 or MSH3 protein, and MLH1 protein complexes with PMS2 or PMS1 protein. MSH6 and PMS2 proteins are unstable when not paired in a complex; thus, a germline mutation in MSH2 typically results in loss of expression of the proteins MSH2/MSH6 and a germline mutation in MLH1 results in loss of expression of the proteins MLH1/PMS2. However, germline mutations in MSH6 and PMS2 typically do not result in loss of MSH2 or MLH1 expression because these proteins are still present in other pairings [Bellizzi & Frankel 2009].
Advantages of IHC testing:
- IHC testing is effective for detecting tumors resulting from MMR deficiency. Antibodies for MSH2, MLH1, MSH6, and PMS2 have demonstrated 92% sensitivity for identifying tumors that arise in individuals with a germline mutation [Shia 2008].
- IHC testing is readily available at most centers and is technically easy to perform.
Limitations of IHC testing:
- Variation in tissue fixation and other technical issues can result in weak or equivocal staining patterns [Shia 2008].
- It may be less reliable when performed on small tissue samples [Zhang 2008].
Microsatellite instability (MSI) testing of tumor tissue. Genes in the mismatch repair (MMR) pathway are responsible for identifying and repairing single nucleotide mismatches and insertion or deletion loops that occur as cells grow and divide [Gruber & Kohlmann 2003]. Defects in the genes involved with mismatch repair lead to an accumulation of somatic mutations in a cell, which may result in the cell becoming malignant.
Microsatellites are stretches of DNA with a repetitive sequence of nucleotides (e.g., AAAAA or CGCGCGCG) that are particularly susceptible to acquiring errors when the mismatch repair gene function is impaired. Cancers arising in cells with defective mismatch repair gene function exhibit an inconsistent number of microsatellite nucleotide repeats when compared to normal tissue, a finding referred to as "microsatellite instability." See Figure 1.
MSI, assessed using a panel of microsatellite markers, is compared in tumor tissue and normal tissue. A 1997 NCI consensus meeting recommended testing a core panel of five markers: BAT25, BAT26, D2S123, D5S346, and D17S250 [Boland et al 1998]. This panel remains the most commonly used, and it includes two mononucleotide and three dinucleotide repeats. However, many labs are now using a variety of panels [Hegde et al 2014]. A tumor continues to be classified as follows [Boland et al 1998, Hegde et al 2014]:
- MSI-high if two or more of the five markers of the core panel show instability or more than 30% of markers show instability in other marker panels.
- MSI-low if one of the five markers in the core panel shows instability or fewer than 30% of markers show instability in other marker panels.
- MSI-stable if 0 (or 0%) of the markers show instability in the core panel or other marker panels.
Note: Although some clinical laboratories use additional markers when performing MSI testing, there is a lack of consensus on the markers beyond the five designed by Boland et al .
- Colon tumors. When adequate tissue is available, studies of Lynch syndrome-associated adenomas suggest a slightly lower rate of MSI compared to invasive cancers, with approximately 80% of adenomas being MSI-high (see Table 3). Adenomas with high-grade dysplasia are more likely to exhibit MSI than early polyps [Iino et al 2000].
- Endometrial cancers. Approximately 20%-30% of endometrial cancers exhibit MSI, and as with colon cancers the majority are the result of somatic MLH1 promoter methylation [Hampel et al 2006].
Advantages of MSI testing:
- MSI testing is an effective method for determining which tumors arise from MMR deficiency. Studies have demonstrated that the sensitivity of MSI testing for identifying tumors that arise in individuals with a germline MMR gene mutation is 93% [Shia 2008].
- MSI testing may be positive (i.e., MSI-high, identifying a tumor as arising from MMR deficiency) when the IHC studies have given a false negative result (e.g., because the appropriate antibody was not included in the test; the protein is present, but nonfunctional) [Shia 2008].
- MSI testing requires very little tissue [Zhang 2008].
- MSI testing is highly reproducible [Zhang 2008].
Limitations of MSI testing:
- It may not be readily available at all centers because it requires microdissection and molecular analysis [Bellizzi & Frankel 2009].
- In some tumors MSI cannot be detected because of technical challenges such as lack of DNA in extremely mucinous tumors [Hampel et al 2005].
- A small portion of Lynch syndrome-related tumors will not show evidence of MMR deficiency [Shia 2008].
- It does not reduce the cost of molecular testing because it does not help identify the gene that is most likely mutated.
- Colon tumors. BRAF pathogenic variants, the most common being NM_004333.4:c.1799T>A (p.Val600Glu, or V600E), occur in 15% of colorectal cancers. BRAF pathogenic variants are thought to be rare in Lynch syndrome-related cancers and, thus, in general the presence of a BRAF pathogenic variant rules out the diagnosis of Lynch syndrome [Bellizzi & Frankel 2009, Bouzourene et al 2010].
- Endometrial cancers. BRAF pathogenic variants are not common in sporadic endometrial cancers; thus, BRAF testing is not helpful in distinguishing endometrial cancers that are sporadic from those that are Lynch syndrome-related [Kawaguchi et al 2009].
Methylation analysis of tumor tissue. The majority of MSI is caused by somatic methylation of the promoter region of MLH1 that silences gene expression in the tumor tissue; thus, the finding of MLH1 promoter methylation can often help eliminate the diagnosis of Lynch syndrome.
However, inactivation of the remaining functional allele by methylation can also be the “second hit” that causes homozygous inactivation of the gene, resulting in tumor development in an individual with a germline MLH1 mutation [Bellizzi & Frankel 2009, Niessen et al 2009]. Therefore, the diagnosis of Lynch syndrome cannot be eliminated by the presence of MLH1 promoter hypermethylation in an individual with early-onset colon cancer, strong family history, or other risk factors.
Somatic methylation of the functional MSH2 allele has been found to be the second hit in approximately 24% of MSH2-related cancers. However, methylation of MSH2 has not been found to be a cause of sporadic colorectal cancers [Nagasaka et al 2010].
Molecular Genetic Testing
Genes. Five genes (MLH1, MSH2, MSH6, PMS2, and EPCAM [formerly known as TACSTD1]) in which germline mutations disrupt the mismatch repair (MMR) pathway and cause Lynch syndrome have been identified (see Table 3).
Note: Although EPCAM is not an MMR gene, recurrent germline deletions of the 3' region result in silencing of the adjacent downstream MSH2 by hypermethylation [Niessen et al 2009, Goel et al 2011, Kuiper et al 2011].
Evidence for additional locus heterogeneity. There are a few case reports of germline MLH3, MSH3, EXO1, PMS1, or TGFBR2 mutations in some families with Lynch syndrome; however, the clinical significance, if any, of allelic variants in these genes in Lynch syndrome has not yet been determined [Lu et al 1998, Peltomaki 2003]. While these and other genes may play a role in the mismatch repair process, there continues to be no confirmed role for mutation testing of these genes as part of a Lynch syndrome evaluation [Thompson et al 2004, Ou et al 2009, Duraturo et al 2011]. A succinct discussion of the evidence for a possible role of these genes in Lynch syndrome can be found at www.omim.org:
The clinical utility of testing for germline mutations in these genes in individuals suspected of having Lynch syndrome is unknown.
To confirm/establish the diagnosis of Lynch syndrome in a proband. To view the Colorectal Cancer Screening testing strategy guidelines developed by the National Comprehensive Cancer Network (NCCN), click (no-cost registration and login required). Testing is ideally performed in a stepwise manner.
I. Testing of Tumor Tissue (Table 2)
MSI and IHC allow for the screening of tumor tissue to help identify individuals who may have Lynch syndrome. These methods may be implemented with various strategies:
Approach 1. Screen all colorectal cancers with MSI and/or IHC testing [EGAPP Working Group 2009].
- A 2005 population-based study of 1566 colorectal cancers reported that 25% of individuals found to have a germline mutation in an MMR gene did not meet the Amsterdam Criteria or Bethesda Guidelines, and therefore a broad-reaching strategy such as universal testing of all diagnosed individuals could be considered.
- Studies have shown that this strategy is increasingly being adopted by academic medical centers and to a lesser extent community hospitals [Beamer et al 2012].
- Success of such programs to identify individuals and families with Lynch syndrome largely depends on the systems in place for following up on abnormal results and ensuring follow through with appropriate genetic counseling and testing [Heald et al 2013].
- The Lynch Syndrome Screening Network was established to help develop best practice approaches for universal screening and to collect long-term data on the outcomes of these programs.
Note: While a combined approach of IHC and MSI testing of tumor tissue is ideal, use of IHC testing alone may be more feasible for large-scale screening programs because it is more readily available than MSI testing and provides information about which MMR gene most likely harbors a germline mutation. For example, for tumors exhibiting loss of both MLH1 and PMS2 expression, reflex testing of tumor tissue for MLH1 promoter methylation and BRAF V600E variants can help distinguish sporadic tumors from those more likely to harbor a germline MLH1 mutation.
Approach 2. Target IHC and/or MSI testing of tumor tissue from individuals with colorectal cancer or other Lynch syndrome-related cancers and additional features that suggest the diagnosis, such as early age of onset or strong family history.
- Research continues to identify factors that may help distinguish the subset of individuals with colorectal and endometrial cancer at greatest risk for Lynch syndrome in order to minimize the costs of screening programs.
- The Bethesda Guidelines were established to help identify individuals who may have Lynch syndrome and who are candidates for MSI and/or IHC testing of tumor tissue [Umar et al 2004]. Although their estimated sensitivity in identifying individuals with Lynch syndrome is up to 94%, their specificity is only 25% [Syngal et al 2000].
- Age of onset and pathologic features have also been used to predict which individuals most likely harbor an MMR pathogenic variant [Rabban et al 2014].
II. Molecular Genetic Testing (Table 3)
Approach 1. As recommended by the results of tumor testing (Table 2)
Approach 2. As per one of the following risk assessment models that help predict the likelihood of identifying a germline mutation in one of the Lynch syndrome associated genes
- PREMM1,2, 6 Model is based on data from 4539 individuals undergoing genetic testing of MSH2, MLH1, and MSH6 through a commercial laboratory. This model incorporates information on the Lynch syndrome-related cancers (colon, endometrial, stomach, ovarian, small intestine, urinary tract/kidney, bile ducts, glioblastoma, sebaceous gland tumors, and pancreas) in the proband and in first and second-degree relatives, and age of onset. Data from MSI and IHC testing are not included. Based on genotype/phenotype data, this model provides specific estimates of the likelhood of detecting a pathogenic variant in each of the MMR genes. Using a 5% mutation probability as a standard for MMR testing, the model has an estimated sensitivity of 90% and a specificity of 54% [Kastrinos et al 2011]. The model is also able to use family history to estimate the likelihood that a person who has not had cancer has a pathogenic variant in an MRR gene.
- MMRpredict is based on data from a population-based cohort diagnosed with colorectal cancer before age 55 years who were tested for pathogenic variants in MLH1, MSH2, and MSH6. Data from MSI and IHC testing and the presence of colorectal and/or endometrial cancer in first-degree relatives can be incorporated. This model can only be used in affected individuals; it is unclear how accurate the model is for tumors diagnosed in older individuals [Barnetson et al 2006].
- MMRpro (see also CancerGene) incorporates information on colorectal and endometrial cancers in the proband and first- and second-degree relatives, age of onset, and results of IHC and MSI testing to estimate the likelihood of identifying a germline mutation in MLH1, MSH2, or MSH6 in a family; uses mendelian modeling to determine the probably that a family member has inherited a germline mutation; and calculates the individual’s risk of developing colon and endometrial cancer.
Pathogenic variant data have been obtained from clinic- and population-based data reported in the literature; cancer risk estimates are based on penetrance data from a meta-analysis of five large Lynch syndrome studies. Since this model does not incorporate information on most extracolonic cancers, it is unclear how accurately it can identify the gene most likely to be mutated [Chen et al 2006].
Approach 3. Foregoing MSI testing and proceeding directly to germline molecular genetic testing in families meeting the Amsterdam Criteria. This approach is becoming more cost effective as next-generation sequencing reduces the cost of testing all MMR genes and EPCAM. However, because there are substantial differences in cancer risk estimates between families with MMR-deficient colon cancer versus MMR-proficient cancers, tumor tissue is often still part of a comprehensive evaluation [Bapat et al 2009]. Direct genetic testing of the MMR genes can be considered in the following situations.
When no tumor tissue is available for tumor testing:
- One strategy for molecular diagnosis of Lynch syndrome is sequential single-gene molecular genetic testing.
- Molecular testing should begin with a family member diagnosed with a Lynch syndrome-related cancer.
- Pursue molecular testing of all four MMR genes and EPCAM. Testing can be done in a stepwise manner beginning with the genes in which a pathogenic variant is most likely to be identified.
- Another strategy is use of a multi-gene panel that evaluates all MRR genes simultaneously. Note: Colon cancer panels may include additional genes not associated with Lynch syndrome.
- The use of a multi-gene panel may provide for efficient identification of pathogenic variants in situations when tumor testing cannot be done to help narrow down the gene involved.
- If no germline mutation is identified in any one of the five genes tested, Lynch syndrome still cannot be ruled out because some pathogenic variants may be missed, or it is possible that the family member selected for testing had a sporadic (non-genetic) cancer. In this latter instance, molecular genetic testing of another relative with a Lynch syndrome-related cancer may result in detection of a causative germline mutation.
- In the absence of information on the MSI status of the tumor, it is not possible to distinguish between Lynch syndrome and other causes of familial colorectal cancer.
When no tumor tissue or living affected relative is available for testing:
- Molecular genetic testing to identify a germline pathogenic variant could be pursued in an unaffected family member.
- The likelihood of an unaffected person having a pathogenic variant (if one is present in the family) depends on that individual's degree of relatedness to an affected family member (e.g., a first-degree relative has a 50% chance of having inherited a pathogenic variant).
- A cost-benefit analysis suggests that testing unaffected individuals is worth pursuing in such instances because of the significant benefit for the family if a Lynch syndrome-causing germline mutation is identified [Dinh et al 2011].
Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM.
Individuals with Lynch syndrome caused by a germline mutation (i.e. pathogenic variant in the germline) in a mismatch repair gene or associated with tumors exhibiting MSI are at increased risk for colon cancer and other cancers including cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin (Table 4).
Colon cancer. Initial studies based on high-risk kindreds meeting Amsterdam criteria have found up to an 82% lifetime risk for colon cancer, and a mean age of onset of 44 years. Two thirds of these cancers occur in the proximal colon [Lynch et al 1993, Lynch & Smyrk 1996, Aarnio et al 1999].
More recent studies of heterozygotes for an MLH1 and MSH2 pathogenic variant have resulted in lower risk estimates of 66%-69% for men and 43%-52% for women, and an average age of diagnosis of 61 years [Hampel et al 2005, Stoffel et al 2009].
Colon cancer risk estimates have also been lower for heterozygotes for an MSH6 and PMS2 pathogenic variant. Risks to male and female heterozygotes for an MSH6 pathogenic variant up to age 80 years have been found to be 44% and 20%, respectively. While substantially lower than the risk associated with MLH1 and MHS2 pathogenic variants, this still represents an eightfold increase in colon cancer risk [Baglietto et al 2010]. The risk to heterozygotes for a PMS2 pathogenic variant up to age 70 years was 15%-20% [Senter et al 2008].
Data on cancer risks for those with an EPCAM pathogenic variant is still limited, but Kempers et al  reported on findings from 194 individuals with an EPCAM deletion. From this cohort they estimated a 75% (95% CI 65-86) cumulative incidence of colorectal cancer by age 70 years. The risk for colorectal cancer did not differ between those who had only a 3’ deletion of EPCAM and those harboring a deletion that encompassed EPCAM and MSH2.
When matched stage for stage, colon cancers in individuals with Lynch syndrome are associated with a better prognosis than sporadic colon cancers [Watson et al 1998], an unexpected finding because the poorly differentiated histology of Lynch syndrome-related colon cancers is typically associated with a poor prognosis. Histologic characteristics of Lynch syndrome-related colon cancers include: poor differentiation, tumor-infiltrating lymphocytes, mucin, and signet ring or cribiform histology.
Endometrial cancer. Women with Lynch syndrome have a 25%-60% lifetime risk of endometrial cancer, making this the second most common cancer in Lynch syndrome [Aarnio et al 1999, Vasen et al 2001, Hampel et al 2005, Stoffel et al 2008]. Studies based on high-risk families have found an average age of diagnosis of approximately 48 years; population-based studies have revealed a later age of diagnosis (62 years) [Vasen et al 1994, Hampel et al 2005].
While mutation of MSH6 is associated with a more moderately increased colon cancer risk, heterozygotes have a 44% risk for endometrial cancer, similar to the level of risk reported for MLH1 and MSH2 heterozygotes [Baglietto et al 2010]. Among women with Lynch syndrome who develop both colon cancer and endometrial cancer, approximately 50% present first with endometrial cancer [Watson et al 1994, Lu et al 2005]. The risk for subsequent endometrial cancer for women with Lynch syndrome presenting first with colon cancer has been estimated at 26% within ten years of the initial colon cancer diagnosis [Obermair et al 2010].
Kemper et al found a 12% (95% CI 0-27) cumulative risk for endometrial cancer by age 70 years. The risk for women with deletions affecting both EPCAM and MSH2 was similar to that reported for women with an MSH2 pathogenic variant [Kempers et al 2011].
Overall, Lynch syndrome accounts for approximately 2% of all endometrial cancers [Hampel et al 2006]. A survival advantage similar to that in Lynch syndrome-related colon cancer has been reported in Lynch syndrome-related endometrial cancers [Maxwell et al 2001].
Gastric cancer. Estimates for gastric cancer risk in heterozygotes for an MLH1 or an MSH2 pathogenic variant range from 6% to 13%. The risk is greatest in males with an MSH2 pathogenic variant [Watson et al 2008, Capelle et al 2010]. Higher risks have been reported in countries with other risk factors for gastric cancer such as high incidence of H pylori infection [Park et al 2000]. The mean age of diagnosis of gastric cancer is 56 years. Intestinal-type adenocarcinoma, the most commonly reported pathology of Lynch syndrome-related gastric cancers [Aarnio et al 1997], differs histologically from the diffuse gastric cancer that is most commonly seen in hereditary diffuse gastric cancer caused by pathogenic variants in CDH1 [Guilford et al 1999]. However, Capelle et al reported that up to 20% of Lynch syndrome-related gastric cancers may be the diffuse type [Capelle et al 2010].
Ovarian cancer. The risk for ovarian cancer varies by the MMR gene in which the germline mutation occurs. The risk to heterozygotes for an MLH1 pathogenic variant has been found to be 4%-6%, while MSH2 heterozygotes have an 8%-11% risk. The mean age of diagnosis of Lynch syndrome-associated ovarian cancers is 42.5 years; however, diagnosis at very young ages has been reported. Approximately 30% of Lynch syndrome-associated ovarian cancers are diagnosed before age 35 years [Watson et al 2008].
The distribution of pathology types is similar to that seen in sporadic ovarian cancers. Borderline ovarian tumors do not seem to be associated with Lynch syndrome [Watson et al 2001].
Other cancers. Other Lynch syndrome-related cancers that have characteristic features have been reported:
- Urinary tract cancers. The urinary tract cancers most commonly associated with Lynch syndrome are transitional carcinomas of the ureter and renal pelvis.
A recent study suggests that bladder cancer risk is likely also increased in Lynch syndrome. A study of a Dutch Lynch syndrome cohort demonstrated a relative risk for bladder cancer of 4.4 for males and 2.2 for females; the majority of tumor tissue available for MSI and/or IHC testing exhibited MSI and/or had loss of protein expression corresponding to the germline mutation [van der Post et al 2010].
Another study of individuals with Lynch syndrome and a prior diagnosis of colorectal cancer also demonstrated an increased risk for bladder cancer (7.22, 95% CI=4.08-10.99) and other urinary tract cancers (kidney, renal pelvis, and ureter) (12.54, 95% CI 7.97-17.94) providing additional evidence that bladder cancer should be included in the Lynch syndrome cancer spectrum [Win et al 2013].
Risk estimates for urinary tract cancers vary significantly based on gender and the mutated gene, with higher risks seen in males heterozygous for an MSH2 pathogenic variant. Women with an MLH1 pathogenic variant have an approximately 1% risk while men with an MSH2 pathogenic variant have been estimated to have up to a 27% risk [Watson et al 2008].
- Small bowel cancer. The risk for small bowel cancer has been estimated at between 3% and 6% [Watson et al 2008]. The duodenum and jejunum are the most common sites for small bowel cancers, with approximately 50% in reach of upper endoscopy [Schulmann et al 2005]. The majority of small bowel cancers are adenocarcinomas [Rodriguez-Bigas et al 1998, Schulmann et al 2005].
- Pancreatic cancer. A study by Kastrinos et al  based on reported family history found an 8.6-fold increased risk up to age 70 years for pancreatic cancer [Kastrinos et al 2009]. A prospective study which followed 446 individuals with an MMR pathogenic variant and 1029 relatives for a median of five years found an increased risk for pancreatic cancer (SIR, 10.68; 95% CI 2.68-47.70), and no increased risk for individuals without a pathogenic variant [Win et al 2012]. However, other studies have not demonstrated an increased risk [Barrow et al 2009]. Lynch syndrome has been found to be a rare cause of familial pancreatic cancer [Gargiulo et al 2009].
- Brain tumors. The risk for brain tumors is estimated at approximately 2% [Schulmann et al 2005]. However, Barrow et al  estimated a 16-fold increased risk for persons with biallelic MSH2 mutations. The most common type of central nervous system tumor is glioblastoma [Hamilton et al 1995, Wimmer & Etzler 2008].
- Sebaceous skin neoplasias described include: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas [Schwartz & Torre 1995, Misago & Narisawa 2000]. Sebaceous neoplasms associated with Lynch syndrome exhibit MSI [Entius et al 2000, Machin et al 2002]. The data on the frequency of sebaceous neoplasms in individuals with Lynch syndrome are limited. Studies have found that between 1% and 9% of individuals with a germline mutation in an MMR gene have a sebaceous neoplasm [Ponti et al 2006, South et al 2008].
- Prostate cancer. Several studies have demonstrated an association with prostate cancer, with the increase in risk ranging from two- to nearly fivefold [Raymond et al 2013b, Haraldsodottir et al 2014, Ryan et al 2014]. Raymond et al [2013b] found that the risk for prostate cancer was increased for men with an MMR pathogenic variant prior to age 60 [Raymond et al 2013b], whereas an analysis by Haraldsdottir et al  found earlier age of onset or a more aggressive phenotype in the prostate cancers occurring in individuals with an MMR pathogenic variant.
- Breast cancer. The relationship between breast cancer and Lynch syndrome is unresolved. A systematic review evaluated 21 studies; 13 did not demonstrate an increased risk for breast cancer in individuals with Lynch syndrome and eight did show an increased risk [Win et al 2013]. To date, breast cancer risk has only been evaluated in one prospective study. Individuals with a pathogenic variant were found to have a standard incidence ratio for breast cancer of 3.95 (95% CI 1.59-8.13), and the median age of breast cancer diagnosis was 56 years. A study by Walsh et al  determined that tissue from 51% of breast cancers in individuals with a pathogenic variant in an MMR gene exhibited loss of immunohistochemical staining for the protein corresponding to the gene in which a germline mutation occurs. Due to the high frequency of breast cancer in the general population, the presence of sporadic breast cancers complicates analysis of the association with Lynch syndrome.
- Additional cancer risks. Several other cancer types have been reported to occur in individuals with Lynch syndrome. In some cases, MSI and/or IHC testing of tumor tissue demonstrated concordance between the extra-colonic cancer and the mutation status of the affected individual. While these types of findings suggest that the underlying presence of a pathogenic variant in an MMR gene contributed to the development of the cancer, data are not sufficient to demonstrate that the risk of developing these types of cancers is increased in individuals with Lynch syndrome.
Several types of sarcomas have been reported in individuals with an MMR pathogenic variant, including fibrous histiocytomas, rhabdomyosarcomas, leiomyosarcoma and liposarcoma [Sijmons et al 2000, den Bakker et al 2003, Nilbert et al 2009]. Nilbert et al  determined that six of eight sarcomas in individuals with Lynch syndrome exhibited defective MMR, suggesting that sarcomas may also be part of the spectrum of Lynch syndrome tumors. Due to the rarity of sarcomas it may be difficult to determine the magnitude of risk associated with Lynch syndrome.
Adrenocortical carcinoma (ACC) has also been reported in families with Lynch syndrome. The most extensive study of this association performed through a hereditary cancer clinic at the University of Michigan found two of 114 (1.7%) individuals presenting with ACC had a family history consistent with Lynch syndrome and had an MMR pathogenic variant identified. This association was further evaluated by case review of 135 individuals with pathogenic MMR variants, which identified two (1.4%) individuals who also had ACC [Raymond et al 2013a].
Lynch syndrome variants
- Muir-Torre syndrome is defined by the combination of sebaceous neoplasms of the skin and one or more internal malignancies, commonly those seen in Lynch syndrome. The types of sebaceous skin neoplasias described include: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas [Schwartz & Torre 1995, Misago & Narisawa 2000].
- Turcot syndrome is defined as colorectal cancer or colorectal adenomas in addition to tumors of the central nervous system. The clinical presentation varies from numerous colonic polyps to a single polyp or colorectal cancer.
Turcot syndrome is usually caused either by a pathogenic variant of APC (see APC-Associated Polyposis Conditions) or by a pathogenic variant in one of the mismatch repair genes associated with Lynch syndrome [Hamilton et al 1995]. Individuals with an APC pathogenic variant typically have more polyps; however, a significant overlap in polyp number occurs between individuals with Turcot syndrome caused by an APC pathogenic variant and those with Turcot syndrome caused by a pathogenic variant in a mismatch repair gene [Hamilton et al 1995]. The pathology of the CNS tumor can help distinguish between the underlying genetic causes: APC pathogenic variants are more commonly associated with medulloblastoma; mismatch repair gene pathogenic variants are more commonly associated with glioblastoma.
The brain tumors associated with mutations in a mismatch repair gene exhibit MSI [Hamilton et al 1995, Suzui et al 1998].
- Homozygous mismatch repair mutations. Rare individuals who are homozygous for pathogenic variants in MLH1, MSH2, MSH6, and PMS2 have been reported. Affected individuals often have onset of colon or small bowel cancer prior to the second decade of life. One third of children with biallelic pathogenic variants in an MMR gene have been reported to have more than ten polyps. Hematologic cancer, brain tumors, and café-au-lait macules have also been reported [Wimmer & Etzler 2008, Durno et al 2010, Bakry et al 2014].
Cancer risks vary among the four MMR genes.
Heterozygosity for an MSH2 pathogenic variant is associated with the greatest risk for extracolonic cancers; risk for extracolonic cancers (other than endometrial cancer) is low for heterozygotes with an MSH6, PMS2, or EPCAM pathogenic variant.
MSH2 pathogenic variants have been reported more commonly than a pathogenic variant in the other three MMR genes in individuals with the Muir-Torre variant of Lynch syndrome [South et al 2008].
Heterozygosity for a pathogenic variant in MSH6 is associated with MSI-low tumors. The cancers in families with an MSH6 pathogenic variant may be later in onset and more distally located than the cancers in families with Lynch syndrome resulting from a pathogenic variant in one of the other MMR genes; endometrial cancer is commonly observed in women with an MSH6 pathogenic variant [Wu et al 1999, Berends et al 2002]. Slightly lower risks for colon cancer and higher risks for endometrial cancer have been reported in families with an MSH6 pathogenic variant than in families with an MLH1 or MSH2 pathogenic variant [Berends et al 2002, Baglietto et al 2010].
Heterozygosity for a PMS2 pathogenic variant is associated with the lowest risk (25%-32% risk) for any Lynch syndrome-related cancer [Senter et al 2008].
Deletions of EPCAM that result in epigenetic silencing of MSH2 are associated with a significantly increased risk for colon cancer. Studies have shown high levels of EPCAM expression in colonic stem cells; however, because EPCAM is not expressed at high levels in all tissues, the effect of EPCAM on extracolonic cancer risks is unclear. Kempers et al  reported a low risk for endometrial cancer in those with deletions of EPCAM compared to mutation of an MMR gene. The risk for extra-colonic cancers also is dependent on the extent of the deletion. 3’ EPCAM deletions have been shown to confer a lower risk for extra-colonic cancers, whereas deletions that extend into MSH2 confer extra-colonic cancer risks similar to intragenic MSH2 pathogenic variants [Tutlewska et al 2013].
Penetrance of colon cancer associated with mutation of an MMR gene or EPCAM is less than 100% (see Table 4). Therefore, some individuals with a cancer-predisposing pathogenic variant in one of the MMR genes never develop colon cancer.
One study reporting anticipation in Lynch syndrome (i.e., offspring having a younger age of onset than the parents) [Westphalen et al 2005] has not been reproduced. Another study in which offspring had a younger age of onset than their parents determined that this observation was caused by birth cohort bias [Tsai et al 1997].
Lynch syndrome has also been called hereditary non-polyposis colorectal cancer (HNPCC). Clinicians and researchers working in the area of hereditary colon cancer have suggested returning to the use of the original name, Lynch syndrome, to specify individuals and families with defective MMR and to distinguish them from other forms of familial colon cancer [Bellizzi & Frankel 2009, Weissman et al 2011].
Familial colorectal cancer. Evaluation of MSI status of tumor tissue is important for differentiating Lynch syndrome from familial colorectal cancer. In studies of families with strong histories of colorectal cancer whose tumors are MSI stable, no increased risk for the extracolonic cancers commonly associated with a germline mutation (pathogenic variant in the germline) in a mismatch repair gene was identified. The risk for colorectal cancer also appears to be lower in families with MSI-stable tumors [Abdel-Rahman et al 2005, Lindor et al 2005, Mueller-Koch et al 2005]. Many candidate genes, low-penetrance alleles, and environmental risk factors have been evaluated with respect to their contributions to familial colorectal cancer.
Attenuated familial adenomatous polyposis (AFAP). This milder presentation of FAP, also caused by pathogenic variants in APC, is characterized by fewer polyps and later age of onset than classic FAP. In AFAP, typically fewer than 100 polyps are observed. Polyps of the gastric fundus and duodenum also occur; however, many of the extracolonic manifestations commonly observed in FAP (e.g., epidermal cysts, dental abnormalities, congenital hypertrophy of retinal pigmented epithelium, desmoid tumors) may be absent in AFAP. Polyps and colon cancers associated with AFAP do not usually exhibit MSI. AFAP is inherited in an autosomal dominant manner.
The APC p.Ile1307Lys pathogenic variant. This missense mutation is not associated with the classic FAP phenotype; however, individuals with the p.Ile1307Lys pathogenic variant in APC are at an approximately twofold increased risk for colon cancer. The pathogenic variant is found in approximately 6% of individuals of Ashkenazi Jewish ancestry [Laken et al 1997]. See APC-Associated Polyposis Conditions for information on this variant.
MUTYH-associated polyposis. Pathogenic variants in MUTYH (MYH) have been described in individuals with multiple adenomatous polyps. Pathogenic variants in MUTYH have been identified in: (1) approximately 30% of individuals with 15-100 polyps; (2) a small portion of individuals with a classic FAP phenotype who have no identifiable APC pathogenic variant; and (3) individuals with a family history of colon cancer in the absence of multiple polyps [Jo et al 2005]. Inheritance is autosomal recessive [Sieber et al 2003].
Hamartomatous polyp syndromes. Several conditions associated with an increased risk for hamartomatous polyps and colon cancer can usually be distinguished by their extracolonic manifestations as well as hamartomatous rather than adenomatous pathology:
- Juvenile polyposis syndrome (JPS), caused by pathogenic variants in SMADA4 and BMPR1A
- Peutz-Jeghers syndrome (PJS), caused by pathogenic variants in STK11
- PTEN hamartomatous syndromes (including Cowden syndrome and Bannayan-Riley-Ruvalcaba [BRR] syndrome), caused by pathogenic variants in PTEN
Hereditary diffuse gastric cancer (HDGC). The gastric cancers, caused by pathogenic variant of CDH1, are typically adenocarcinomas.
BRCA1/BRCA2 hereditary breast/ovarian syndrome should be considered when evaluating an individual with a family history of cancer that includes ovarian cancer.
Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Lynch syndrome, the evaluations summarized in Surveillance are recommended.
Treatment of Manifestations
Management of colon cancer in a person with Lynch syndrome. If colon cancer is detected, full colectomy with ileorectal anastomosis is recommended rather than a segmental/partial colonic resection because of the high risk for metachronous cancers [Lynch et al 1988, Aarnio et al 1995, Church & Simmang 2003]. A study of 296 individuals (253 with partial resection, 43 with colectomy anastomosis) from families meeting Amsterdam Criteria found that with a median follow up of 104 months, 22% of affected individuals treated with a partial resection developed a high-risk adenoma and 25% developed a second primary colon cancer, while only 11% and 8% of affected individuals developed adenomas and colon cancers respectively [Kalady et al 2010]. Note: Because the diagnosis of Lynch syndrome is often not considered until after treatment of an initial cancer, many individuals diagnosed with Lynch syndrome have previously had their cancer treated with a limited colonic resection.
Although timing may be difficult, evaluating the tumor biopsy specimen by MSI and IHC (and, if indicated, the MHL1 promoter methylation status) may help determine the optimal surgical approach. A study suggests that persons with colon cancer are open to being approached about genetic testing at the time of their diagnosis [Porteous et al 2003].
The other tumors seen in Lynch syndrome are managed as in the general population.
Prevention of Primary Manifestations
Prophylactic removal of the uterus and ovaries (prior to the development of cancer) can be considered after childbearing is completed.
Because routine colonoscopy is an effective preventive measure for colon cancer, prophylactic colectomy (removal of the colon prior to the development of cancer) is generally not recommended for individuals with Lynch syndrome.
Colon cancer. Regular colonoscopy with removal of precancerous polyps reduces the incidence of colon cancer in individuals with Lynch syndrome. A 2009 study of a Finish cohort with high compliance with screening found no increase in mortality for individuals with Lynch syndrome over their mutation-negative relatives, indicating that annual colonoscopy could help with the prevention and detection of colon cancer [Järvinen et al 2009]. In this study four individuals were diagnosed with colon cancer and lymph node metastases: one was diagnosed during baseline colonoscopy; the other three were diagnosed more than two years after their last colonoscopy. Therefore, the current recommendation is colonoscopy every one to two years beginning between ages 20 and 25 years or two to five years before the earliest diagnosis in the family, whichever is earlier [Järvinen et al 2009, Engel et al 2010, NCCN 2013].
Note: Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in Lynch syndrome [Lynch & Smyrk 1996].
Endometrial cancer. Endometrial cancer surveillance is less well established than that for colon cancer.
Because many endometrial cancers can be diagnosed at early stages on the basis of symptoms, women should be educated about the signs of endometrial cancers.
Currently the National Comprehensive Cancer Network (NCCN) does not recommend any specific screening for endometrial or ovarian cancer [NCCN 2013].
Studies on the effectiveness of transvaginal ultrasound examination and endometrial biopsy have had conflicting results. Further studies are needed to determine if the combination of transvaginal ultrasound examination and endometrial biopsy detect endometrial cancers at an early age.
- In a study of the use of transvaginal ultrasound examination to screen for endometrial cancer, no cancers were detected; however, two cancers were detected on the basis of symptoms manifest during the course of the study [Dove-Edwin et al 2002].
- A report from a Finnish cohort found that endometrial sampling and transvaginal ultrasound every two to three years resulted in the diagnosis of early stage cancers. However, because endometrial cancer often presents with symptoms at an early stage, it was not clear that the screening improved detection [Järvinen et al 2009].
Ovarian cancer. No specific ovarian cancer screening trials have been conducted in women with Lynch syndrome. Of note, screening for ovarian cancer using CA-125 blood tests and transvaginal ultrasound examination has not been effective in other high-risk populations such as women with a BRCA1 or BRCA2 pathogenic variant [Evans et al 2009].
Gastric and duodenal cancers. Upper endoscopy surveillance can be used to screen for cancers of the stomach and duodenum. Currently the NCCN recommends beginning upper endoscopy with a side-viewing scope and extended duodenoscopy between ages 30 and 35 years and repeating them every three to five years depending on the findings. Those with evidence of chronic inflammation, atrophic gastropathy, and/or intestinal metaplasia would be candidates for more frequent evaluation. Note: Biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed [NCCN 2013].
Data regarding the effectiveness of upper endoscopy examination for the early detection of gastric cancer in Lynch syndrome are limited.
- One study suggested no benefit from this screening for gastric cancer because of the lack of identifiable precursor lesions [Renkonen-Sinisalo et al 2002].
- A study looking at gastric cancer risk in a Dutch study suggested that the level of risk is sufficient to warrant screening; however, since 87% of the cancers occurred after age 45 years, it may be most cost effective to initiate screening at age 45 years [Capelle et al 2010].
- Schulmann et al  found that approximately 50% of the small bowel cancers in a cohort with Lynch syndrome were located in the duodenum, suggesting that upper endoscopy may be useful for screening. However, no trials to determine the efficacy of upper endoscopy for screening for duodenal cancers have been conducted.
Distal small bowel. At this time data are limited regarding screening for cancer development in the distal small bowel. Capsule endoscopy and small bowel enterography are available for evaluating the small bowel, but at this time there is no recommendation for routine use of these approaches for small bowel screening, although they may be helpful for evaluating symptomatic individuals.
Urinary tract. NCCN recommends consideration of annual urine analysis beginning between age 25 and 30 years [NCCN 2013].
Other cancers. At this time, no specific screening recommendations for other Lynch syndrome associated cancers exist. Affected individuals should be encouraged to follow other general population screening guidelines and to seek prompt medical attention for changes in health or persistent symptoms.
Agents/Circumstances to Avoid
Evaluation of Relatives at Risk
Early recognition of cancers associated with Lynch syndrome may allow for timely intervention and improved final outcome; thus, surveillance of asymptomatic at-risk relatives for early manifestations is appropriate.
When an MMR pathogenic variant has been identified in a family with Lynch syndrome, molecular genetic testing for the pathogenic variant should be offered to all first-degree relatives (parents, sibs, and children).
- The sibs should be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited (not de novo) mutation.
- If clinical history and family history cannot identify the parent from whom the proband inherited the MMR gene pathogenic variant, molecular genetic testing for the pathogenic variant should be offered to both parents to determine which has the MMR gene mutation.
In general, molecular genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, because cancer has been diagnosed in individuals with Lynch syndrome at very young ages [Huang et al 2001], it is recommended that screening begin ten years before the earliest age of onset in the family. In such instances, it is appropriate to offer molecular genetic testing to children younger than age 18 years prior to initiating cancer screening.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Ideally cancer screening exams would be planned around a pregnancy. An affected woman would be encouraged to be current on her cancer screening before attempting to become pregnant. If an affected woman is diagnosed with cancer during pregnancy, she should be counseled about cancer treatment options and their potential implications for the fetus.
Therapies Under Investigation
Chromoendoscopy and intensive colonoscopy. A 2008 study compared the effectiveness of chromoendoscopy and intensive colonoscopy inspection in early detection of polyps in persons with Lynch syndrome. Following standard colonoscopy, study participants were randomized to receive a second colonoscopy with chromoendoscopy or a second colonoscopy with careful inspection. This study found that although polyps are frequently missed during standard colonoscopy, no difference was observed between the number of additional polyps detected by chromoendoscopy and by the careful second-look colonoscopy [Stoffel et al 2008]. Further studies are needed to determine if novel colonoscopy techniques confer additional benefit for the screening of persons with Lynch syndrome.
Chemoprevention research studies
- A four-arm trial comparing placebo versus aspirin and placebo versus resistant starch was conducted among 1071 individuals with Lynch syndrome. No effect on the risk for colorectal neoplasia was seen in either the aspirin or resistant starch intervention group [Burn et al 2008]. However, when this cohort was followed for ten years, the group receiving aspirin did show a 63% reduction in colon cancer incidence [Burt 2012]. Resistant starch was not found to have an impact on colon cancer risk [Mathers et al 2012].
- Whereas oral contraceptives reduce the risk for endometrial and ovarian cancer in women who are at general population risk, it is unknown if they confer the same benefit in women with Lynch syndrome.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Lynch syndrome is inherited in an autosomal dominant manner.
Risk to Family Members
Parents of a proband
- The majority of individuals diagnosed with Lynch syndrome have inherited the pathogenic variant from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from screening or prophylactic surgery, or early death, not all individuals with mutation of a Lynch syndrome-causing MMR gene have a parent who had cancer.
- If clinical and family history cannot identify the parent from whom the proband inherited the MMR pathogenic variant, molecular genetic testing should be offered to both parents to determine which one has the pathogenic variant identified in the proband.
- The precise new mutation rate for Lynch syndrome is unknown but estimated to be extremely low [Bisgaard & Bernstein 2003].
Sibs of a proband
- Sibs of a proband are at a 50% risk of inheriting the pathogenic variant.
- Molecular genetic testing for the pathogenic variant identified in the family should be offered to all sibs.
- The sibs should still be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited, not a de novo, mutation.
Offspring of a proband. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the pathogenic variant.
Other family members of a proband. The risk to other family members depends on their relationship to the proband. Family history or molecular genetic testing can help determine whether maternal or paternal relatives are at risk. Offspring of family members found to have pathogenic variants or diagnosed with Lynch syndrome-related cancers can be assumed to be at 50% risk. For branches of the family in which the at-risk person died without developing a cancer, Bayesian analysis can be used to help calculate the risk to the offspring.
Related Genetic Counseling Issues
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
Specific risk issues. Several factors can hinder the diagnosis of Lynch syndrome based on family history. Screening and removal of precancerous polyps and prophylactic surgery may prevent colon or endometrial cancer in some at-risk relatives; some who died young from other causes may never have developed cancer.
Considerations in families with apparent de novo mutation. When neither parent of a proband with Lynch syndrome has the pathogenic variant or clinical evidence of Lynch syndrome, it is possible that the proband has a de novo mutation. However, de novo mutation in an MMR gene is thought to be rare and other possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored [Bisgaard & Bernstein 2003].
- The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ®, National Cancer Institute).
Testing of at-risk asymptomatic adults for Lynch syndrome is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity and type of symptoms, or rate of disease progression will be. When testing at-risk individuals for Lynch syndrome, an affected family member should be tested first to confirm the molecular diagnosis in the family.
Genetic counseling is recommended prior to making decisions about genetic testing. Brain et al  suggest that a single educational session may be adequate for genetic counseling for asymptomatic adults who are at risk for treatable conditions. However, preparatory information may be helpful in encouraging individuals to reflect on issues not previously considered. Genetic counseling includes discussion of the clinical and psychosocial implications of genetic testing for the individual and for family members. Studies assessing psychological adjustment following genetic testing have not found that learning that one has a Lynch syndrome pathogenic variant is associated with adverse psychological outcomes or clinically significant increases in distress. However, subgroups of individuals with Lynch syndrome, such as those with high levels of pre-test distress, poor quality of life, or low levels of social support, are at greater risk of experiencing psychological morbidity [Vernon et al 1997, Dudok de Wit et al 1998, Gritz et al 1999].
Molecular genetic testing of asymptomatic individuals younger than age 18 years. In general, genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. Guidelines established jointly by the American College of Medical Genetics and the American Society of Human Genetics state that predictive genetic testing should be performed in individuals younger than age 18 years only if it will affect their medical management. It is recommended that the decision to test be postponed until an individual reaches adulthood and can make an independent decision because management for cancer risk associated with Lynch syndrome is not recommended to begin until age 20 years. Since there are rare reported cases of individuals with Lynch syndrome diagnosed with cancer at very young ages [Huang et al 2001], it is recommended that screening begin ten years before the earliest age of onset in the family. In some families, individuals may need to begin screening before age 18 years. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
Prenatal diagnosis for pregnancies at increased risk for Lynch syndrome is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for typically adult-onset conditions which (like Lynch syndrome) have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA)
- Lynch Syndrome InternationalP.O. Box 5456Vacaville CA 95688Phone: 707-689-5089Email: email@example.com
- National Cancer Institute (NCI)6116 Executive BoulevardSuite 300Bethesda MD 20892-8322Phone: 800-422-6237 (toll-free)Email: firstname.lastname@example.org
- American Cancer Society (ACS)1599 Clifton Road NortheastAtlanta GA 30329-4251Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
- C3: Colorectal Cancer Coalition1414 Prince StreetSuite 204Alexandria VA 22314Phone: 877-427-2111 (toll-free); 703-548-1225Fax: 202-315-3871Email: email@example.com
- Colon Cancer Alliance (CCA)1200 G Street NorthwestSuite 800Washington DC 20005Phone: 877-422-2030 (Toll-free Helpline); 202-434-8980Fax: 866-304-9075 (toll-free)
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
|114500||COLORECTAL CANCER; CRC|
|120435||LYNCH SYNDROME I|
|120436||MutL, E. COLI, HOMOLOG OF, 1; MLH1|
|158320||MUIR-TORRE SYNDROME; MRTES|
|185535||EPITHELIAL CELLULAR ADHESION MOLECULE; EPCAM|
|276300||MISMATCH REPAIR CANCER SYNDROME; MMRCS|
|600259||POSTMEIOTIC SEGREGATION INCREASED, S. CEREVISIAE, 2; PMS2|
|600678||MutS, E. COLI, HOMOLOG OF, 6; MSH6|
|609309||MutS, E. COLI, HOMOLOG OF, 2; MSH2|
|609310||COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2; HNPCC2|
|613244||COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 8; HNPCC8|
Molecular Genetic Pathogenesis
Lynch syndrome is caused by pathogenic variants in genes involved with the mismatch repair (MMR) pathway. This pathway functions to identify and remove single nucleotide mismatches or insertions and deletion loops. Pathogenic variants in four of the MMR genes can cause Lynch syndrome [Peltomaki 2003]. The functions of the mismatch repair genes can be disrupted by missense mutations, truncating mutations, splice site mutations, large deletions, or genomic rearrangements. In addition, germline deletion within EPCAM, which is not an MMR gene, can disrupt the MMR pathway by inactivating the adjacent MMR gene MSH2, even though MSH2 itself has not been mutated.
Genetic modifiers of cancer risk in Lynch syndrome have been reported:
- Zecevic et al  found that shorter IGF1-CA repeats are associated with an increased risk (HR=2.36; 95% CI=1.28 to 4.36) for colon cancer and earlier age of onset (44 vs. 56.5 years) among individuals who have a pathogenic variant in an MMR gene.
- A variant of RNASEL has also been reported to be associated with an earlier age of onset, with an average age of onset of 40 years for individuals homozygous for the Arg462 variant and 34 years for individuals homozygous for the Gly462 variant [Kruger et al 2005].
- Pande et al  evaluated a number of genes including CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 and found that two sequence variants in CYP1A1 may contribute to earlier age of colon cancer onset in individuals with Lynch syndrome.
- Analysis of several single nucleotide polymorphisms reported to be associated with colorectal cancer risk were not found to modify the cancer risk in individuals with MMR pathogenic variants [Win et al 2013].
Gene structure. MLH1 is 57,357 kb in length, with 19 coding exons encoding a protein of 756 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.
Pathogenic allelic variants. More than 200 different pathogenic variants have been reported in MLH1 [Peltomaki 2003, Peltomaki & Vasen 2004]; see Table A. Deletions account for 5%-10% of germline MLH1 mutations (i.e., pathogenic variants in the germline).
Constitutional inactivation of MLH1 by methylation, along with somatic loss of heterozygosity of the functional allele, has been reported as a rare cause of Lynch syndrome (~0.6%) [Niessen et al 2009]. These individuals have silencing of one MLH1 allele, throughout their tissues, due to methylation of the promoter and a Lynch syndrome phenotype. Most of such cases are simplex (i.e., a single occurrence in a family), but a few cases of inherited hypermethylation have been reported [Goel et al 2011]. These cases are not detectable by either sequence analysis or duplication/deletion analysis of MLH1.
Normal gene product. DNA mismatch repair protein Mlh1 dimerizes with the product of the PMS2 gene (PMS1 protein homolog 2) to coordinate the binding of other proteins involved with mismatch repair including the helicases, the protein encoded by EXO1, proliferating cell nuclear antigen (PCNA), single-stranded-DNA binding-protein (RPA), and DNA polymerases [Peltomaki 2003].
Abnormal gene product. MLH1 acts in a recessive manner at the cellular level where there is an absence of functional Mlh1 protein in the tumor cells. This results from inactivation of both MLH1 alleles in the tumor, which often occurs as a result of an inactivating mutation or silencing of the MLH1 promoter by hypermethylation.
Gene structure. MSH2 comprises 16 exons encoding a protein of 934 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.
Pathogenic allelic variants. More than 170 pathogenic variants have been identified in MSH2 [Peltomaki 2003, Peltomaki & Vasen 2004]. The higher proportion of Alu repeats may contribute to the higher rate of genomic rearrangements in MSH2 than in MLH1 [van der Klift et al 2005]. At least 20% of germline MSH2 mutations are exonic or multiexonic deletions.
Normal gene product. DNA mismatch repair protein MSH2, the protein encoded by MSH2, forms a heterodimer with either DNA mismatch repair protein MSH6 or MSH3 and functions to identify mismatches. A sliding clamp model has been suggested to describe the structure of the heterodimer. Mismatches in the DNA are thought to be detected as the clamp slides along the DNA [Fishel et al 1993, Gruber & Kohlmann 2003].
Abnormal gene product. MSH2 acts in a recessive manner at the cellular level where there is an absence of functional Msh2 protein in the tumor cells. This results from inactivation of both MSH2 alleles in the tumor, which often occurs by the mechanism of loss of heterozygosity (LOH). MSH2 promoter methylation has been shown to be the inactivating event that silences the normal allele in individuals with an MSH2 inactivating pathogenic variant. Of note, this is not a common cause of sporadic colon cancer.
Gene structure. MSH6 comprises ten exons encoding a protein of 1360 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.
Pathogenic allelic variants. More than 30 pathogenic variants have been identified in MSH6 [Peltomaki & Vasen 2004]. Exonic or mult-exonic deletions are a rare cause of germline MSH6 mutations.
Normal gene product. The protein encoded by MSH6, DNA mismatch repair protein MSH6, forms a heterodimer with DNA mismatch repair protein MSH2 and functions to identify mismatches by a sliding clamp model [Fishel et al 1993, Gruber & Kohlmann 2003].
Abnormal gene product. MSH6 acts in a recessive manner at the cellular level where there is an absence of functional MSH6 protein in the tumor cells. This results from inactivation of both MSH6 alleles in the tumor, which often occurs by the mechanism of loss of heterozygosity (LOH).
Gene structure. PMS2 comprises 15 exons encoding a protein of 862 amino acids. Multiple pseudogenes have been identified at 7p22, 7p12-13, 7q11, and 7q22 [Nicolaides et al 1995]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.
Pathogenic allelic variants. Germline mutations in PMS2 are rare [Hendriks et al 2006]. Single nucleotide variants and large gene rearrangements have been reported. Studies that have included large deletion testing have found that up to 20% of pathogenic variants may be large deletions (Table 3). Large deletion testing of PMS2 is technically difficult due to numerous pseudogenes and it presents significant challenges to laboratories trying to provide comprehensive large deletion testing for the whole gene. The currently available MLPA (multiplex ligation-dependent probe amplification) kit can detect deletions but does not clarify whether the deletion may be in one of the pseudogenes. Testing in coordination with a panel of reference samples can help determine whether deletions are clinically significant [Vaughn et al 2011].
Normal gene product. See MLH1, Normal gene product.
Abnormal gene product. PMS2 acts in a recessive manner at the cellular level where there is an absence of functional PMS2 protein in the tumor cells. This results from inactivation of both PMS2 alleles in the tumor, which often occurs by the mechanism of loss of heterozygosity (LOH).
Gene structure. EPCAM comprises nine exons encoding a protein of 314 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.
Pathogenic allelic variants. Deletions involving the transcription termination signal of EPCAM are causative in 1% to 2.8% of families with Lynch syndrome. Other EPCAM pathogenic variants that do not affect the transcription termination signal cause autosomal recessive congenital tufting enteropathy [Sivagnanam et al 2010].
Normal gene product. EPCAM expression varies in tissues. High levels of expression were found in colorectal stem cells while low levels of expression were detected in leukocytes [Ligtenberg et al 2009]. Little is known about EPCAM expression in most other tissues predisposed to Lynch syndrome-related cancers.
Abnormal gene product. EPCAM deletions are thought to arise from Alu-mediated recombination events [Kuiper et al 2011]. Elimination of the EPCAM transcription termination signal results in transcription continuing into MSH2 and silencing of the MSH2 promoter by methylation. Through this mechanism the MSH2 allele in cis configuration with the EPCAM deletion becomes inactivated in the tissues in which EPCAM is expressed, while the other MSH2 allele is unaffected. These pathogenic variants are transmitted in an autosomal dominant manner, as are germline mutations in genes involved in MMR [Ligtenberg et al 2009].
Published Guidelines/Consensus Statements
- American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 5-19-14.
- American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC). Available online. 2003. Accessed 5-19-14.
- American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 5-19-14. [PMC free article: PMC1801355] [PubMed: 7485175]
- American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available online. 2000. Accessed 5-19-14.
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- 22 May 2014 (me) Comprehensive update posted live
- 20 September 2012 (cd) Revision: Multi-gene panels for Lynch syndrome (hereditary non-polyposis colon cancer) available clinically
- 11 August 2011 (me) Comprehensive update posted live
- 29 November 2006 (me) Comprehensive update posted to live Web site
- 5 February 2004 (me) Review posted to live Web site
- 18 April 2003 (sg) Original submission
Salt Lake City, Utah
Los Angeles, California
Initial Posting: February 5, 2004; Last Update: May 22, 2014.
University of Washington, Seattle, Seattle (WA)
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