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MSH2 gene
URL of this page: https://medlineplus.gov/genetics/gene/msh2/

MSH2 gene

mutS homolog 2

Normal Function

The MSH2 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps correct errors that are made when DNA is copied in preparation for cell division, a process called DNA replication. The MSH2 protein joins with another protein to form a two-protein complex called a dimer. This complex identifies locations where errors have been made during DNA replication. The MSH2 dimer, together with another dimer and additional proteins, makes the repairs by replacing the section of DNA that contains an error with a corrected DNA sequence. The MSH2 gene is one of a set of genes called mismatch repair (MMR) genes.

Health Conditions Related to Genetic Changes

Constitutional mismatch repair deficiency syndrome

Genetic changes that cause a disease or increase the risk for a disease are sometimes called mutations or pathogenic variants. Pathogenic variants in the MSH2 gene have been associated with a condition called constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD greatly increases a person's risk of developing cancer throughout their lifetime, beginning in early childhood. The most common cancers that occur in people with CMMRD are cancers of the blood (leukemia or lymphoma), brain, and colon and rectum (collectively referred to as colorectal cancer).  Approximately 50 percent of people with CMMRD will develop cancer by age 10, and 90 percent will develop cancer by age 18. Many people with CMMRD develop additional features, including changes in skin coloring (pigmentation).

People must inherit a pathogenic variant in both copies of the MSH2 gene (one from each parent) to have CMMRD. The parents of these individuals inherit a pathogenic variant in only one copy of the MSH2 gene and have a condition called Lynch syndrome (described below). People with Lynch syndrome have an increased risk of developing cancer in adulthood. Because people with CMMRD inherit a pathogenic variant in both copies of the MSH2 gene, the production of functional MSH2 protein is impaired in all cells of the body. The absence of functional MSH2 protein disrupts the body’s ability to fix errors made during DNA replication. DNA errors accumulate in all cells, which increases the risk of cancer in people with CMMRD.

More About This Health Condition

Lynch syndrome

Pathogenic variants in the MSH2 gene can also cause a condition called Lynch syndrome. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer and cancer of the lining of the uterus. People with Lynch syndrome also have an increased risk of cancers of the ovaries, stomach, small intestine, gallbladder ducts, upper urinary tract, and brain. By age 70, the risk of developing cancer is approximately 77 percent in people who have Lynch syndrome caused by variants in the MSH2 gene. It is estimated that up to 40 percent of people who receive a diagnosis of Lynch syndrome have a pathogenic variant in the MSH2 gene.

People with Lynch syndrome caused by variants in the MSH2 gene typically inherit a normal MSH2 gene from one parent and an MSH2 gene with a pathogenic variant from the other parent. Individuals with one normal copy of the MSH2 gene typically produce enough functional MSH2 protein to repair DNA errors.

However, problems can occur if the normal copy of the MSH2 gene acquires a pathogenic variant during a person’s lifetime. These acquired variants are present only in certain cells and are not inherited. In people with Lynch syndrome caused by an MSH2 pathogenic variant, cells that acquire a pathogenic variant in the normal copy of the MSH2 gene will no longer produce enough functional MSH2 protein. Without enough functional MSH2 protein, these cells are not able to fix errors made during DNA replication. These DNA errors accumulate as the cell continues to divide and may alter the activity of other genes involved in cell growth and division. These changes increase the risk of cancer in people with Lynch syndrome.

Some variants in the MSH2 gene cause a form of Lynch syndrome called Muir-Torre syndrome. In addition to colorectal cancer, people with this condition have an increased risk of developing several uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in the glands that produce an oily substance called sebum (sebaceous glands). Rapidly growing tumors called keratoacanthomas may also occur, usually on sun-exposed areas of skin.

More About This Health Condition

Other Names for This Gene

  • COCA1
  • FCC1
  • MSH-2

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

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