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PMS2
PMS1 homolog 2, mismatch repair system component
The PMS2 gene provides instructions for a protein that is a key component of the DNA mismatch repair system, responsible for correcting errors during DNA replication. The PMS2 gene plays a vital role in maintaining genomic integrity by ensuring accurate DNA replication.
PMS2 is located on the short (p) arm of chromosome 7, at band 7p22.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The PMS2 gene, formally known as PMS1 homolog 2, mismatch repair system component, encodes a protein critical for DNA mismatch repair (MMR). This repair mechanism is essential for correcting errors that can arise when DNA is copied, a process known as DNA replication. The PMS2 protein helps prevent the accumulation of mutations, maintaining the stability of the genome [PMID:15866171].
Dysfunction of the PMS2 gene is associated with an increased susceptibility to certain types of cancer. It is recognised within the ACMG SF v3.2 classification as a gene for which secondary findings are clinically actionable (Tier 1), highlighting its importance in inherited cancer predisposition.
What the gene does
The PMS2 gene product is an integral part of the DNA mismatch repair (MMR) system, a sophisticated cellular mechanism designed to correct errors occurring during DNA replication. Specifically, the PMS2 protein forms a dimer with the MLH1 protein, creating a complex crucial for identifying and excising mispaired nucleotides or small insertion/deletion loops within the newly synthesised DNA strand [PMID:8552403]. This MLH1-PMS2 complex coordinates communication between other proteins involved in the repair process.
After an error is detected, the MMR complex facilitates the removal of the incorrect DNA segment. The complex also directs the replacement of this segment with the correct sequence. This intricate process prevents the incorporation of mutations into the genome, which could otherwise lead to cellular dysfunction or uncontrolled cell growth. The overall efficiency and accuracy of DNA replication heavily rely on the proper functioning of the PMS2 protein and its interactions within the MMR pathway, making it a critical guardian of genomic stability [PMID:11389843].
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Chromosome location
The PMS2 gene is situated on chromosome 7, specifically at position 7p22.1. This region of the chromosome also houses several non-functional DNA sequences, known as pseudogenes, which bear a high degree of similarity to the functional PMS2 gene. The presence of these pseudogenes can complicate genetic analysis of the PMS2 gene, as genetic material can be exchanged between the functional gene and its pseudogenes. This exchange may lead to alterations within the PMS2 gene sequence, often referred to as gene conversion events, which can be challenging to accurately detect and interpret in diagnostic testing.
Protein structure
The PMS2 protein is composed of 862 amino acids, contributing to its role in DNA mismatch repair. Structural analysis reveals key regions that dictate its function. The protein contains a Disordered region spanning amino acids 391-552. Additionally, a Nuclear localisation signal (Motif) is identified within amino acids 577-580. This motif is crucial for directing the PMS2 protein to the nucleus, where it performs its essential DNA repair functions alongside other components of the mismatch repair machinery.
Key variants
Genetic variations within the PMS2 gene can range from single nucleotide changes to larger structural rearrangements. Pathogenic variants, often referred to as mutations, can disrupt the normal function of the PMS2 protein, leading to an impaired DNA mismatch repair system. These impairments can result in an increased rate of errors during DNA replication, leading to genomic instability and a heightened risk of developing certain medical conditions. The identification and classification of PMS2 variants are critical for understanding disease risk and guiding clinical management. The presence of highly similar pseudogenes near the functional PMS2 gene poses unique challenges for variant detection and interpretation, requiring specialised testing approaches to accurately distinguish true PMS2 variants from pseudogene sequences.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.354-?_(*160_?)del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.804-?_2006+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-87)_1144+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-87)_23+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.904-?_1144+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.904-?_(*160_?)del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.989-?_(*160_?)del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.1169_1170ins20 | p.? | Pathogenic | ★★★☆ | Mismatch repair cancer syndrome 4 |
c.1021del | p.Arg341fs | Pathogenic | ★★★☆ | Lynch syndrome 4 |
c.1076dup | p.Leu359fs | Pathogenic | ★★★☆ | Lynch syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the PMS2 gene are primarily associated with an increased predisposition to cancer. The most notable condition is Lynch syndrome (PMS2), an inherited disorder that significantly raises the risk of various cancers, particularly colorectal and endometrial cancers. PMS2 variants have been reported in constitutional mismatch repair deficiency syndrome, though the full clinical characterisation of this association remains under investigation.
Inheritance pattern
Conditions caused by pathogenic PMS2 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, PMS2 is a recognised gene within the NHS Genomic Medicine Service, indicating its clinical significance for inherited conditions. It is included in numerous NHS England National Genomic Test Directory panels, covering a wide range of cancer susceptibilities. These include panels for Adult solid tumours cancer susceptibility, Bladder cancer pertinent cancer susceptibility, Colorectal cancer pertinent cancer susceptibility, and Inherited MMR deficiency (Lynch syndrome) (R210), among others. Its presence on these panels ensures that genetic testing for PMS2 variants is available for individuals suspected of having hereditary cancer predispositions, facilitating diagnosis and guiding patient management within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that adopted lifestyle choices, including dietary habits and physical activity, can influence overall health for individuals with an increased genetic predisposition to certain conditions. For the general population, maintaining a balanced diet rich in fruits, vegetables, and whole grains, combined with regular physical activity, is associated with a reduced risk of various chronic diseases, including some cancers. Limiting consumption of red and processed meats, as well as maintaining a healthy body weight, are also commonly recommended lifestyle strategies for cancer prevention. While these general health recommendations are beneficial, they do not negate genetic risk factors, and individuals with a PMS2 pathogenic variant should engage in discussions with their healthcare provider regarding personalised risk management strategies and surveillance protocols.
Supplement considerations
Currently, there is no conclusive scientific evidence that specific dietary supplements can prevent or treat conditions associated with PMS2 pathogenic variants. While some supplements are marketed for general 'gut health' or 'cancer prevention', robust clinical evidence supporting these claims is limited. Individuals considering taking any supplements should consult with a healthcare professional to discuss potential interactions with existing medications, possible side effects, and whether the supplement is appropriate for their specific health needs. A balanced diet generally provides sufficient nutrients for most people.
Frequently asked questions
What does the PMS2 gene do?
The PMS2 gene provides instructions for making a protein that plays a critical role in the DNA mismatch repair (MMR) system. This system corrects errors that occur when DNA is copied, helping to maintain the stability of the genetic code.
What conditions are associated with PMS2 variants?
Pathogenic variants in the PMS2 gene are primarily associated with Lynch syndrome, which increases the risk of colorectal, endometrial, and other cancers. PMS2 variants have also been reported in constitutional mismatch repair deficiency syndrome.
How is PMS2 related to Lynch syndrome?
PMS2 is one of the key genes associated with Lynch syndrome. Pathogenic variants in PMS2 can impair the DNA mismatch repair process, leading to an accumulation of mutations and a significantly increased lifetime risk of developing Lynch-associated cancers.
Can PMS2 gene variants be tested for?
Yes, genetic testing can identify pathogenic variants in the PMS2 gene. These tests are available through various clinical pathways, including those offered by the NHS Genomic Medicine Service for individuals suspected of having inherited cancer predispositions.
What is the importance of the PMS2 protein's nuclear localisation signal?
The nuclear localisation signal in the PMS2 protein is essential for directing the protein into the cell's nucleus. This is where DNA replication and repair take place, so proper nuclear targeting ensures the PMS2 protein can perform its crucial mismatch repair functions.
Does lifestyle affect PMS2-related cancer risk?
While lifestyle factors like diet and exercise can influence overall cancer risk in the general population, evidence suggests they do not eliminate the increased genetic risk conferred by a PMS2 pathogenic variant. Individuals with such a variant should discuss personalised risk management with their healthcare provider.
References
- Dominguez-Valentin M, Sampson JR, Seppälä TT. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genetics in medicine : official journal of the American College of Medical Genetics. 2020. PMID: 31337882
- Ten Broeke SW, van der Klift HM, Tops CMJ. Cancer Risks for PMS2-Associated Lynch Syndrome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018. PMID: 30161022
- Goodenberger ML, Thomas BC, Riegert-Johnson D. PMS2 monoallelic mutation carriers: the known unknown. Genetics in medicine : official journal of the American College of Medical Genetics. 2016. PMID: 25856668
- Wimmer K, Kratz CP, Vasen HF. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). Journal of medical genetics. 2014. PMID: 24737826
- Senter L, Clendenning M, Sotamaa K. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008. PMID: 18602922
- Hendriks YM, Jagmohan-Changur S, van der Klift HM. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology. 2006. PMID: 16472587
- Truninger K, Menigatti M, Luz J. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology. 2005. PMID: 15887099
- Peltomäki P. Lynch syndrome genes. Familial cancer. 2005. PMID: 16136382
- Gill S, Lindor NM, Burgart LJ. Isolated loss of PMS2 expression in colorectal cancers: frequency, patient age, and familial aggregation. Clinical cancer research : an official journal of the American Association for Cancer Research. 2005. PMID: 16166421
- Lynch HT, de la Chapelle A. Hereditary colorectal cancer. The New England journal of medicine. 2003. PMID: 12621137
- Adam MP, Bick S, Mirzaa GM. Lynch Syndrome. 1993. PMID: 20301390