MSH6 gene

The MSH6 gene provides instructions for a protein that is vital for DNA repair, helping to correct errors that occur during cell division.

Normal Function

The MSH6 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 MSH6 protein joins with another protein called MSH2 to form a two-protein complex called a dimer. This complex identifies locations where errors have been made during DNA replication. The MSH2-MSH6 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 MSH6 gene is one of a set of genes called mismatch repair (MMR) genes.

Health Conditions Related to Genetic Changes

Constitutional mismatch repair deficiency syndrome

Pathogenic variants in the MSH6 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.

People must inherit a pathogenic variant in both copies of the MSH6 gene (one from each parent) to have CMMRD. Because people with CMMRD inherit a pathogenic variant in both copies of the MSH6 gene, the production of functional MSH6 protein is impaired in all cells of the body. The absence of functional MSH6 protein disrupts the body’s ability to fix errors made during DNA replication, leading to an accumulation of DNA errors and an increased risk of cancer.

Lynch syndrome

Pathogenic variants in the MSH6 gene can also cause 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. It is estimated that up to 35 percent of people who receive a diagnosis of Lynch syndrome have a pathogenic variant in the MSH6 gene.

People with Lynch syndrome caused by variants in the MSH6 gene typically inherit a normal MSH6 gene from one parent and an MSH6 gene with a pathogenic variant from the other parent. Individuals with one normal copy of the MSH6 gene typically produce enough functional MSH6 protein to repair DNA errors. However, problems can occur if the normal copy of the MSH6 gene acquires a pathogenic variant during a person’s lifetime. Cells that acquire a pathogenic variant in the normal copy will no longer produce any functional MSH6 protein, preventing the cell from fixing DNA replication errors and increasing the risk of cancer.

Other Names for This Gene

• G-T binding protein
• G/T mismatch-binding protein
• GTBP
• MSH-6