A PMS2 mutation is a change in a specific gene that helps maintain the integrity of our genetic material. PMS2 is one of the four main genes associated with Lynch Syndrome, an inherited condition that increases the risk of developing certain cancers, particularly those affecting the colon and uterus.
How the PMS2 Gene Functions
The PMS2 gene functions as a component of the Mismatch Repair (MMR) system, which acts as the cell’s internal proofreader. This system scans the DNA strand after replication to correct errors naturally incorporated by the DNA polymerase enzyme. The MMR system ensures the DNA sequence remains stable and accurate across cell generations.
The PMS2 protein typically partners with the MLH1 protein to create the MutL-alpha complex. When a mismatch is detected, this complex is recruited, and the PMS2 protein acts as an endonuclease to nick the newly synthesized DNA strand near the error. This nick allows specialized enzymes to excise and remove the incorrect DNA segment, which is then correctly resynthesized. If a PMS2 mutation renders the protein non-functional, this repair mechanism fails, leading to an accumulation of replication errors and microsatellite instability. This genetic instability drives the development of cancer over time.
Inheritance and Associated Syndromes
Mutations in the PMS2 gene can be inherited in two patterns, leading to different clinical syndromes and cancer risks. The most common presentation is Lynch Syndrome, caused by inheriting one altered copy of the PMS2 gene from one parent in an autosomal dominant pattern. Individuals with this heterozygous mutation retain one functional copy, resulting in a higher but manageable lifetime cancer risk that typically manifests in adulthood.
A much rarer condition is Constitutional Mismatch Repair Deficiency (CMMR-D), which occurs when an individual inherits a mutated copy of the PMS2 gene from both parents. This autosomal recessive pattern means the individual has two non-functional copies, leading to a complete breakdown of the MMR system. CMMR-D is characterized by an extremely high cancer risk and the onset of malignancies, often alongside symptoms like café-au-lait spots on the skin, almost exclusively during childhood. A CMMR-D diagnosis indicates both parents are carriers of a PMS2 mutation, requiring them to undergo appropriate Lynch Syndrome surveillance.
Cancer Risks in Mutation Carriers
The cancer risks for PMS2 mutation carriers vary depending on whether the mutation is heterozygous (Lynch Syndrome) or homozygous (CMMR-D). For individuals with Lynch Syndrome, the lifetime risk of developing colorectal cancer is estimated to be between 12% and 22% by age 80. The risk for endometrial (uterine) cancer is approximately 13%. These cancer risks are generally lower, and the age of onset is later, compared to mutations in other Lynch Syndrome genes, such as MLH1 or MSH2.
While colorectal and endometrial cancers are the most clearly associated malignancies, PMS2 carriers may also have a slightly increased risk for other cancers, including ovarian, gastric, and small intestine cancers. The overall cancer spectrum for PMS2-related Lynch Syndrome is considered the mildest among the MMR genes, but the risk warrants proactive medical management. Conversely, children with homozygous CMMR-D syndrome face a cancer risk greater than 90% by age 20, with the mean age of first tumor diagnosis around 7.5 years. The cancer spectrum in CMMR-D is broad, including brain tumors, acute leukemias, and lymphomas, in addition to the colorectal and gynecological cancers seen in Lynch Syndrome.
Genetic Testing and Diagnosis
The identification of a PMS2 mutation often begins with initial screening of a tumor sample if cancer is already present. This screening typically involves Immunohistochemistry (IHC), a technique that uses antibodies to look for the presence or absence of MMR proteins in the tumor tissue. The loss of PMS2 protein expression in a tumor suggests an inherited PMS2 mutation may be the underlying cause.
If IHC results indicate a potential MMR defect, germline testing is performed on a non-cancerous tissue sample, usually blood or saliva, to confirm the inherited status. Genetic testing involves sequencing the entire MMR gene panel, focusing specifically on the PMS2 gene. Testing for PMS2 is technically challenging due to the presence of a pseudogene, PMS2CL, which is a non-functional copy with a highly similar sequence. Specialized sequencing methods are necessary to distinguish between the functional gene and the pseudogene to accurately confirm the mutation status.
Ongoing Management and Screening
Confirmed carriers of a heterozygous PMS2 mutation require an intensive surveillance program that begins much earlier than standard cancer screening guidelines. For colorectal cancer, this involves a colonoscopy starting between the ages of 30 and 35, repeated every one to two years. This schedule is designed to detect polyps or early-stage cancer when treatment is most effective.
Women with a PMS2 mutation also require specialized gynecological surveillance for endometrial cancer, which may include annual endometrial biopsies and transvaginal ultrasounds starting between ages 30 and 35. Risk-reducing surgery, such as a hysterectomy and removal of the ovaries and fallopian tubes, is often discussed after childbearing is complete. Management for CMMR-D carriers requires specialized pediatric oncology teams who implement comprehensive surveillance protocols tailored to the aggressive cancer spectrum seen in children with a complete MMR deficiency.