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 colorectal and other cancers, including endometrial, gastric, ovarian, pancreas, urothelial, brain (usually glioblastoma), biliary tract, small intestine, as well as sebaceous skin lesions and keratoacanthomas. 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, through age 80, associated with Lynch syndrome mutations

NE: Not well-established

Adapted from: NCCN v.1.2023

Prevalence of LS

About 2-4% of colorectal cancers and 0.8-1.4% of endometrial cancers can be attributed to Lynch syndrome. An estimated 1 in 300 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.

Diagnosis

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

Genetics & Inheritance

LS is 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.

While rare, individuals with Lynch syndrome mutations should be aware that if they have a child with another person who also has Lynch syndrome, the child has a 25% chance of carrying two mutations in the same gene, causing Constitutional Mismatch Repair Deficiency (CMMRD), characterized by brain, blood, gynecological, and certain pediatric cancers.

Clinical Testing

Clinical testing options include tumor analysis with 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 screening using IHC and/or MSI, and proceed to multigene testing. 

Tumor Analysis

Immunohistochemistry (IHC) or microsatellite instability (MSI) screening for mismatch repair deficiency (dMMR) on the tumor sample is recommended for individuals with colorectal or endometrial cancer, and can be considered for other cancers. 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 unstable 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, standard of care includes IHC for all newly diagnosed CRC and EC specimens. MSI maybe the screening method of choice in certain situations where the result could affect treatment decisions; patients with confirmed mismatch repair deficiency may be eligible for immunotherapy.

Depending on tumor screening results, additional tumor tests (BRAF V600E analysis and/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 EPCAM. Often these genes are analyzed as part of a larger multigene hereditary cancer panel.

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

Genetic Testing and Referral Criteria

The NationalComprehensive Cancer Network (NCCN) guidelines list referral cirteria.

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

• Known LS mutation in family
• Personal history of colorectal or endometrial cancer diagnosed before age 50
• Personal history of a tumor with MMR deficiency at any age
• An individual with a ≥2.5% risk of having a LS gene mutation using predictive models including those with a personal history of colorectal or endometrial cancer
• 3 or more individuals with CRC or LS-associated cancers at any age
• 2 individuals with CRC or LS-associated cancers, with at least one diagnosed before age 50 years
• 1 or more individuals with
  • CRC diagnosed at a younger than usual age (< 50 years), or
  • Two primary cancers: CRC or endometrial cancer and a LS-associated cancer

Management

Early and increased surveillance (colonoscopy and endometrial biopsy, among other screening) and consideration of risk reducing interventions (such as preventive hysterectomy and oophorectomy) are recommended,as well as consideration of targeted therapeutics for afected patients. 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 Jeghers 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. While genetic testing with a multigene panel can detect variants for these risks as well as for Lynch syndrome, 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

Resources

American Society of Clinical Oncology (2021): Lynch Syndrome.

Medline/Genetics Home Reference (2021): Lynch Syndrome.

Guidelines

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. (see Addendum, 2019).

American College of Obstetrics and Gynecology (2019): Committee Opinion #793. Hereditary Cancer Syndromes and Risk Assessment.

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.

National Comprehensive Cancer Network (v.1.2023): Genetic/Familial High Risk Assessment: Colorectal (free registration required for access).

US Multi-Society Task Force (2015): Guidelines on Genetic Evaluation and Management of Lynch Syndrome.

Updated August 2023