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PMS2 gene
URL of this page: https://medlineplus.gov/genetics/gene/pms2/

PMS2 gene

PMS1 homolog 2, mismatch repair system component

Normal Function

The PMS2 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 PMS2 protein joins with another protein called MLH1 to form a two-protein complex called a dimer. This complex coordinates the activities of other proteins that are involved in repairing errors made during DNA replication. The section of DNA that contains an error is removed and replaced with a corrected DNA sequence. The PMS2 gene is one of a set of genes called mismatch repair (MMR) genes.

The PMS2 gene is located on chromosome 7. Chromosome 7 also contains several nonfunctional pieces of DNA called pseudogenes that are similar to the PMS2 gene. The PMS2 gene can exchange genetic material with one of the pseudogenes that is located very close to the PMS2 gene. This exchange of genetic information can lead to changes in the PMS2 gene and can complicate genetic testing that involves this region of chromosome 7. 

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 PMS2 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). Pathogenic variants in the PMS2 gene are found in more than 50 percent of people who receive a diagnosis of CMMRD, making PMS2 pathogenic variants the most common cause of CMMRD.

People must inherit a pathogenic variant in both copies of the PMS2 gene (one from each parent) to have CMMRD. The parents of these individuals inherit a pathogenic variant in only one copy of the PMS2 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 PMS2 gene, the production of functional PMS2 protein is impaired in all cells of the body. The absence of functional PMS2 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 PMS2 gene have been reported in some families with Lynch syndrome. Lynch syndrome increases the risk of many types of cancer, including colorectal cancer and cancer of the lining of the uterus. By age 70, the risk of developing cancer for people with Lynch syndrome that is caused by a PMS2 gene variant is approximately 22 percent. Individuals who have Lynch syndrome caused by a PMS2 gene variant typically have a lower risk of developing colorectal cancer and tend to develop colorectal cancer later in life than people who have Lynch syndrome caused by variants in other genes. It is estimated that fewer than 25 percent of people who receive a diagnosis of Lynch syndrome have a pathogenic variant in the PMS2 gene. 

People with Lynch syndrome caused by variants in the PMS2 gene typically inherit a normal PMS2 gene from one parent and a PMS2 gene with a pathogenic variant from the other parent. Individuals with one normal copy of the PMS2 gene typically produce enough functional PMS2 protein to repair DNA errors.

However, problems can occur if the normal copy of the PMS2 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 a PMS2 pathogenic variant, cells that acquire a pathogenic variant in the normal copy of the PMS2 gene will no longer produce enough functional PMS2 protein. Without enough functional PMS2 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.

More About This Health Condition

Other Names for This Gene

  • Mismatch repair gene PMSL2
  • MLH4
  • PMS-2
  • PMSL2

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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