MLH1 gene: MedlinePlus Genetics (original) (raw)

Normal Function

The MLH1 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 MLH1 protein joins with another protein called PMS2 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 MLH1 gene is one of a set of genes called mismatch repair (MMR) genes. The MLH1 protein can also form a dimer with the MLH3 or PMS1 protein, but the function of these dimers is not well understood.

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 MLH1 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 who have 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 MLH1 gene (one from each parent) to have CMMRD. The parents of these individuals inherit a pathogenic variant in only one copy of the MLH1 gene and have a condition called Lynch syndrome (described below). People who have Lynch syndrome have an increased risk of developing cancer in adulthood. Because people with CMMRD have a pathogenic variant in both copies of the MLH1 gene, the production of functional MLH1 protein is impaired in all cells of the body. The absence of functional MLH1 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

Several hundred different MLH1 pathogenic variants have been found in people with 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, people with Lynch syndrome caused by variants in the MLH1 gene have a 65 to 80 percent risk of developing cancer. It is estimated that up to 40 percent of people who receive a diagnosis of Lynch syndrome have a pathogenic variant in the MLH1 gene.

People with Lynch syndrome caused by pathogenic variants in the MLH1 gene typically inherit a normal MLH1 gene from one parent and an MLH1 gene with a pathogenic variant from the other parent. Individuals with one normal copy of the MLH1 gene typically produce enough functional MLH1 protein to repair DNA errors.

However, problems can occur if the normal copy of the MLH1 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 MLH1 pathogenic variant, cells that acquire a pathogenic variant in the normal copy of the MLH1 gene will no longer produce any functional MLH1 protein. Without enough functional MLH1 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.