Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare disorder that greatly increases the risk of developing one or more types of cancer in children and young adults. The cancers that most commonly occur in CMMRD syndrome are cancers of the colon (large intestine) and rectum (collectively referred to as colorectal cancer), brain, and blood (leukemia or lymphoma).

Almost all people with CMMRD syndrome develop cancer before age 18, generally in late childhood. The age of diagnosis varies depending on the cancer type; brain cancers, leukemia, and lymphomas tend to occur at younger ages than colorectal cancer in people with CMMRD syndrome. It is estimated that 20 to 40 percent of people with CMMRD syndrome who develop cancer will develop another cancer later in life.

People with CMMRD syndrome may develop multiple noncancerous (benign) growths (adenomas) in the colon that are likely to become cancerous (malignant) over time. Brain cancers in CMMRD syndrome often involve certain cells called glial cells, causing gliomas or glioblastomas. The most common blood cancer in CMMRD syndrome is called non-Hodgkin lymphoma, which affects white blood cells. Other cancers that can occur in CMMRD syndrome include cancers of the small intestine, urinary tract, or uterine lining (endometrial cancer).

Many people with CMMRD syndrome develop features similar to those that occur in a condition called neurofibromatosis type 1. These features include changes in skin coloring (pigmentation), which are characterized by one or more flat patches on the skin that are darker than the surrounding area (café-au-lait spots). Some affected individuals have freckling or patches of skin that are unusually light in color (hypopigmented). Rarely, people with CMMRD syndrome will develop a feature of neurofibromatosis type 1 called Lisch nodules, which are benign growths that often appear in the colored part of the eye (the iris). Lisch nodules do not interfere with vision. Some people with CMMRD syndrome are initially misdiagnosed with neurofibromatosis type 1.

Mutations in the PMS2 gene are the most common cause of CMMRD syndrome, and mutations in the MLH1, MSH2, or MSH6 gene cause the remaining cases. These four genes are involved in repairing errors that occur when DNA is copied in preparation for cell division (a process called DNA replication). Because these genes work together to fix DNA errors, they are known as DNA mismatch repair (MMR) genes.

Mutations in any of these genes result in near or complete loss of functional protein. A shortage of one of these proteins eliminates mismatch repair activity and prevents the proper repair of errors that occur during DNA replication. The errors accumulate and disrupt other genes involved in important cellular processes such as controlling cell growth and division (proliferation). Uncontrolled cell growth can lead to childhood cancer in people with CMMRD syndrome.

It is thought that the features of neurofibromatosis type 1 in people with CMMRD syndrome are due to genetic changes in the NF1 gene that result from a loss of mismatch repair. These changes are present only in certain cells (somatic mutations), whereas NF1 gene mutations that are present in all cells of the body cause neurofibromatosis type 1.

Normal Function

The PMS2 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The PMS2 protein joins with another protein called MLH1 (produced from the MLH1 gene) to form a two-protein complex called a dimer. This complex coordinates the activities of other proteins that repair errors made during DNA replication. Repairs are made by removing the section of DNA that contains errors and replacing it with a corrected DNA sequence. The PMS2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

Health Conditions Related to Genetic Changes

Constitutional mismatch repair deficiency syndrome

More than 55 variants (also known as mutations) in the PMS2 gene have been associated with a condition called constitutional mismatch repair deficiency (CMMRD) syndrome. PMS2 gene variants are the most frequent cause of this condition. Individuals with CMMRD syndrome are at increased risk of developing cancers of the colon (large intestine) and rectum (collectively referred to as colorectal cancer), brain, and blood (leukemia or lymphoma). These cancers usually first occur in childhood, with the vast majority of cancers in CMMRD syndrome diagnosed in people under the age of 18. Many people with CMMRD syndrome also develop changes in skin coloring (pigmentation), similar to those that occur in a condition called neurofibromatosis type 1.

Individuals with CMMRD syndrome inherit two PMS2 gene variants, one from each parent, while people with Lynch syndrome (described below) have a variant in one copy of the PMS2 gene.

PMS2 gene variants result in near or complete loss of PMS2 protein production. A shortage of this protein eliminates mismatch repair activity and prevents the proper repair of DNA replication errors. These errors accumulate as the abnormal cells continue to divide. The errors disrupt other genes involved in important cellular processes, such as controlling cell growth and division (proliferation). If cell growth is uncontrolled, it can lead to childhood cancer in people with CMMRD syndrome.

It is thought that the features of neurofibromatosis type 1 in people with CMMRD syndrome are due to genetic changes in the NF1 gene that result from loss of mismatch repair. These changes are present only in certain cells (somatic variants), whereas NF1 gene variants that are present in all cells of the body cause neurofibromatosis type 1.

Lynch syndrome

Variants in the PMS2 gene have been reported in about 6 percent of families with Lynch syndrome that have an identified gene alteration. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the endometrium (lining of the uterus), ovaries, stomach, small intestine, liver, gallbladder ducts, upper urinary tract, and brain. By age 75, the risk of developing one of these cancers is 30 percent for women and 25 percent for men with a PMS2 gene variant. These variants lead to a form of Lynch syndrome with a lower risk of cancer development compared to other causes of this condition. Additionally, in people with a PMS2 gene variant, cancer tends to occur at a later age compared to others with Lynch syndrome. The reason for this lower cancer risk is unclear.

PMS2 gene variants involved in this condition lead to the production of an abnormally short or inactive PMS2 protein from one copy of the gene. The altered protein cannot efficiently repair errors made during DNA replication. The errors accumulate as the cells continue to divide, increasing the risk of tumor formation in the colon or another part of the body.

Because there is some functional PMS2 protein produced from the normal copy of the gene, mismatch repair activity in Lynch syndrome is reduced but not absent, as it is in CMMRD syndrome (described above). This difference in DNA repair activity levels likely explains why cancers in Lynch syndrome generally develop in adulthood while those in CMMRD syndrome often affect children.

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Other Names for This Gene

• PMS2 postmeiotic segregation increased 2 (S. cerevisiae)
• PMS2_HUMAN
• postmeiotic segregation increased (S. cerevisiae) 2

Genomic Location

CMMRD syndrome is inherited in an autosomal recessive pattern, which means having mutations in both copies of the gene greatly increases the risk of developing cancer. The parents of an individual with CMMRD syndrome each carry one copy of the mutated gene.

A single mutation in any of the genes associated with CMMRD syndrome generally leads to a different cancer predisposition syndrome called Lynch syndrome. Because the parents of an individual with CMMRD syndrome typically have a single copy of the mutated gene, they may have Lynch syndrome. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer, but also cancers of the stomach, small intestine, gallbladder ducts, upper urinary tract, endometrium, brain, and skin. Unlike CMMRD syndrome, individuals with Lynch syndrome often develop these cancers in adulthood. Additionally, not all people with Lynch syndrome develop cancerous tumors, so a person with CMMRD syndrome might not have a history of cancer in their family.

CMMRD syndrome is a rare disorder; more than 200 affected individuals have been reported in the scientific literature.