Lynch Syndrome Factsheet

Clinical Features

Lynch syndrome (LS) is an adult-onset, cancer predisposition syndrome. It is caused by a mutation in one of the genes involved in the mismatch repair (MMR) pathway. Individuals with LS are at increased risk for colon and other cancers, including gastric, urinary tract, brain, small bowel, pancreatic, hepatobiliary and sebaceous carcinoma. Women with LS are at increased risk for endometrial and ovarian cancer. Individuals with LS tend to have cancer at an earlier age than the general population, and have higher risk for metachronous colorectal cancer and a second primary tumor in a different tissue. Lynch syndrome is not associated with any unique physician exam findings.

Cancer Risks to Age 70 Associated with LS


Cancer Type

Lynch carrier
MLH1/MSH2 mutation

Lynch carrier
MSH6/PMS2 mutation

General Population

















Small bowel


Not reported


Urinary tract




Hepatobiliary tract


Not reported


Central nervous system


Not reported




Not reported



1-6% Not reported



Prevalence of LS

About 1-3% of colorectal cancers and 0.8-1.4% of endometrial cancers can be attributed to Lynch. An estimated 1 in 300-1,000 individuals in the general population have LS. Statistical algorithms are available to determine the likelihood of a Lynch-associated mutation based on personal and family history.


An individual should meet clinical criteria (see below) or have a mutation identified through molecular testing of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or EPCAM gene.

Clinical Criteria

The Amsterdam II criteria define the minimum requirements for a clinical diagnosis of Lynch syndrome:

  • There should be at least three relatives with a Lynch-associated cancer (cancer of the colorectum, endometrium, small bowel, ureter or renal pelvis)
  • Familial adenomatous polyposis should be excluded
  • Tumors should be verified by pathological examination

The Amsterdam criteria have high specificity for LS, but low sensitivity. Not all families with LS will meet these criteria. 

Genetics & Inheritance

LSis caused by a mutation in a mismatch repair (MMR) gene, which includes MLH1, MSH2, MSH6, and PMS2, or the EPCAM gene, which is involved in MMR gene expression. MMR is a DNA repair process in which the MMR proteins correct errors that occur during DNA replication. 

LS is an autosomal dominant condition. First-degree relatives of a mutation carrier have a 50% chance of also carrying the mutation. Men and women are equally likely to inherit, and pass on, a mutation.

Clinical Testing

Clinical testing options include tumor analysis of immunohistochemistry (IHC) and/or microsatellite instability (MSI) and molecular analysis of the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. In general, the recommended testing protocol for an individual with cancer is to begin with tumor analysis using IHC and/or MSI, and proceed to targeted gene testing based on tumor results. 

Tumor Analysis

Immunohistochemistry (IHC) or microsatellite instability (MSI) testing on the tumor sample is recommended for individuals with colorectal or endometrial cancer. These tests can be performed by a pathologist on archived tumor blocks from a surgical specimen.

  • IHC testing can detect the presence or absence of the protein products of the mismatch repair genes. A missing protein suggests a mutation in the gene that codes for that protein. 83% of individuals with LS have abnormal IHC results.
  • MSI testing can detect an abnormal number of microsatellite repeats, which indicates that the cancer more likely arose from cells with defective MMR genes. A result of “MSI-high” means that a high number of microsatellite repeats were found. 90% of individuals with LS have MSI-high results. 

IHC and MSI are screening tests and, if positive, indicate that germline genetic testing is appropriate to determine which MMR gene is mutated. Increasingly, it is becoming standard of care for IHC to be performed on all newly-diagnosed CRC and select EC specimens.

Depending on tumor screening results, additional tumor tests (BRAF V600E analysis or MLH1 promoter methylation analysis) may be indicated to further rule-out Lynch syndrome, and in many cases, eliminate the need for germline genetic testing. 

Genetic Testing

Germline molecular testing includes sequencing and deletion/duplication analysis of MLH1, MSH2, MSH6, PMS2, and/or EPCAM. Molecular testing is most informative and cost effective when performed after initial tumor screening using MSI/IHC. 

See the NCCN guidelines and GeneReviews below for a suggested tumor and genetic testing strategy.

Genetic Testing and Referral Criteria

Meeting one or more of the criteria below warrants further risk assessment, genetic counseling and genetic testing as appropriate:

  • Known LS mutation in family
  • Meets Amsterdam II criteria (see Clinical Criteria above)
  • Absent expression of MMR proteins on IHC or MSI-H in tumor
  • Colorectal or endometrial cancer diagnosed under 50
  • Presence of ≥2 LS-associated cancers in an individual
  • Colorectal cancer diagnosed in a patient with ≥ 1 first-degree relatives with a LS-associated cancer, with one of the cancers being diagnosed before age 50
  • Colorectal cancer diagnosed in a patient with ≥ 2 first- or second-degree relatives with LS-related cancers at any age


Increased surveillance (colonoscopy and endometrial biopsy, among other screening) and consideration of risk reducing interventions (such as chemoprevention and preventive hysterectomy and oophorectomy) are recommended. Published guidelines are available. See NCCN for more information about management.

Other Genes that Contribute to Colon Cancer

There are other hereditary cancer syndromes that increase the risk for colorectal cancer, such as Familial Adenomatous Polyposis (FAP), MUTYH-associated polyposis (MAP), Peutz Jegher Syndrome, Juvenile Polyposis Syndrome and Cowden Syndrome. The presentation of these syndromes in a family may overlap with that of Lynch, but can sometimes be distinguished based on characteristic features, such as physical exam findings and polyp burden. In addition, a number of common genetic susceptibility variants are thought to increase colon cancer risk to a lesser extent than the MMR genes and EPCAM. There are likely other genes that contribute to colon cancer which have not yet been identified. See GeneReviews for more information about the genetic differential diagnosis for LS. 

Select Guidelines & Resources


GeneReviews (2014): Lynch syndrome.

American Society of Clinical Oncology (2014): Lynch syndrome.


National Comprehensive Cancer Network (2016): Genetic/Familial High Risk Assessment: Colorectal (Free registration required for access).

American College of Gastroenterology (2015): Clinical Guideline on Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes.

American College of Gastroenterology (2015): Clinical Guideline on Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes.

American College of Medical Genetics & National Society of Genetic Counselors (2014): Referral indications for cancer predisposition assessment.

American Society of Clinical Oncology & Society of Surgical Oncology (2006): ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes.

American Society of Colon and Rectal Surgeons & Collaborative Group of the Americans on Inherited Colorectal Cancer (2003): Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer).

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009): Recommendations from the EGAPP Working Group: Genetic Testing Strategies in Newly Diagnosed Individuals with Colorectal Cancer Aimed at Reducing Morbidity and Mortality from Lynch Syndrome Relatives.

International Collaborative Group on HNPCC (1999): New Clinical Criteria For Hereditary Nonpolyposis Colorectal Cancer (HNPCC, Lynch Syndrome).

National Cancer Institute (2004): Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability.