An MSH6 mutation is a change in the MSH6 gene, which provides instructions for a protein that helps repair errors in DNA. This gene acts as a “genetic spell-checker” for our body. Each time a cell divides, it copies its DNA, and mistakes can happen during this process. The MSH6 gene’s job is to find and fix these mistakes to keep the genetic code accurate.
A mutation in this gene means the instructions are flawed, leading to a less effective protein. When this spell-checker doesn’t work correctly, errors can accumulate in the DNA of new cells, which can lead to health issues over time.
The Function of the MSH6 Gene
The MSH6 gene is a component of the body’s DNA Mismatch Repair (MMR) system. This system is a group of genes that work together to protect the integrity of our genetic code. The primary function of the MMR system is to correct errors made during DNA replication, such as mismatched base pairs or small insertions and deletions.
To perform its function, the protein made by the MSH6 gene partners with another protein, MSH2, to form a complex called MutS alpha. This complex scans newly synthesized DNA, looking for specific types of errors like single base-pair mismatches. Once MutS alpha identifies a mistake, it flags the location and recruits other proteins to remove the incorrect section and replace it with the correct DNA sequence, which is integral to maintaining genetic stability.
Associated Health Risks and Lynch Syndrome
A mutation in the MSH6 gene is primarily associated with an inherited condition called Lynch syndrome. Lynch syndrome is a hereditary cancer predisposition syndrome that results from mutations in DNA mismatch repair genes. Because the cell’s ability to correct DNA errors is reduced, individuals with an MSH6 mutation have an increased lifetime risk of developing certain types of cancer.
The most prominent cancers associated with MSH6-related Lynch syndrome are colorectal and endometrial. For women with an MSH6 mutation, the lifetime risk of developing endometrial cancer can be as high as 40%, while the risk for colorectal cancer is around 20%. For men, the lifetime risk of colorectal cancer is approximately 10%, and these cancers tend to occur at a younger age than in the general population.
Other cancers are also linked to MSH6 mutations, although the risks are lower. These include an increased risk for ovarian, stomach, urinary tract, pancreatic, and certain skin cancers. Compared to mutations in other Lynch syndrome genes, such as MLH1 and MSH2, mutations in MSH6 are associated with a lower overall cancer risk and a later age of cancer onset. This distinction is meaningful for tailoring medical monitoring and management strategies.
Inheritance Patterns and Family Considerations
The MSH6 mutation is passed down in an autosomal dominant inheritance pattern. This means a person only needs to inherit one copy of the mutated gene from either parent to have the associated risks. A parent who carries the mutation has a 50% chance of passing it on to each of their children.
This inheritance pattern has significant implications for family members. If an individual has an MSH6 mutation, their parents, siblings, and children also have a chance of carrying it. Communicating this genetic information within the family allows relatives to pursue their own testing and make informed health decisions, a process known as “cascade testing.”
It is also possible, though rare, for a person to inherit two mutated copies of the MSH6 gene. This leads to a more severe condition called Constitutional Mismatch Repair Deficiency (CMMRD), characterized by a high risk of developing cancers in childhood. Genetic counseling can help individuals understand their risks and the potential risks for their relatives.
Screening and Management for Carriers
For carriers of an MSH6 mutation, medical management is focused on early detection and risk reduction. Plans are personalized but involve increased surveillance for the cancers most strongly associated with Lynch syndrome. This proactive approach allows for the detection of precancerous growths or early-stage cancers, when treatment is most effective.
The primary surveillance for MSH6 carriers is regular colonoscopy, starting between ages 30 and 35 and repeated every one to two years. For women, screening for endometrial and ovarian cancer is also recommended, starting around the same age. This may include annual transvaginal ultrasounds and endometrial biopsies.
Beyond surveillance, individuals can discuss risk-reducing options with their healthcare team. Prophylactic surgeries, such as a hysterectomy to prevent endometrial cancer or an oophorectomy to prevent ovarian cancer, are options some women consider after childbearing. Daily aspirin use has also been shown to lower the risk of colorectal cancer in people with Lynch syndrome, though this should be discussed with a doctor.