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MSH6
mutS homolog 6
The MSH6 gene provides instructions for a protein critical to DNA mismatch repair, playing a vital role in correcting errors that occur during DNA replication. MSH6 is a key component of the mismatch repair (MMR) system, forming a complex with MSH2 to identify and correct replication errors.
MSH6 is located on the short (p) arm of chromosome 2, at band 2p16.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The MSH6 gene, also known as mutS homolog 6, encodes a protein essential for maintaining genomic stability. It is a core component of the DNA mismatch repair (MMR) pathway, a critical cellular mechanism responsible for correcting errors that arise during DNA replication.
Dysfunction of the MSH6 protein can lead to an accumulation of genetic errors, significantly increasing an individual's susceptibility to certain types of cancer. Pathogenic variants in MSH6 are associated with Lynch syndrome and constitutional mismatch repair deficiency syndrome [PMID:33671077].
What the gene does
The MSH6 gene directs the synthesis of a protein pivotal in the DNA mismatch repair (MMR) system [PMID:28213619]. When DNA is copied during cell division, occasional errors can occur where incorrect nucleotide bases are incorporated into the new strand. The MSH6 protein works with the MSH2 protein to form a two-protein complex called a dimer, specifically known as MutS alpha.
This MSH2-MSH6 complex is primarily responsible for recognising and binding to these erroneous base mismatches and replication errors within the DNA double helix. Once identified, the MutS alpha complex recruits other proteins of the MMR pathway to excise the incorrect DNA segment and synthesise a corrected replacement. This precise repair mechanism ensures the fidelity of genetic information passed on during cell division.
The MSH6 protein's ability to accurately detect these replication errors is fundamental to preventing the accumulation of somatic mutations. A compromised MMR system, due to pathogenic variants in MSH6, can result in cells accumulating mutations at an increased rate, thereby increasing the risk of cancer development.
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Chromosome location
The MSH6 gene is situated on the short arm of chromosome 2, specifically at position 2p16.3. This chromosomal location indicates its precise address within the human genome. The MSH6 gene spans a region of DNA that contains the instructions for producing the full-length MSH6 protein, which consists of 1360 amino acids.
Protein structure
The MSH6 protein, comprising 1360 amino acids, exhibits a modular structure with several distinct regions and domains. An initial Disordered region is located at the N-terminus, spanning amino acids 1-84. Following this, a PWWP domain is found between amino acids 92 and 154. Another Disordered region is present from amino acids 195 to 362. These structural elements contribute to the protein's overall conformation and its interactions within the DNA mismatch repair complex.
Key variants
Variants within the MSH6 gene can encompass a wide range of genetic changes, including single nucleotide changes, small insertions or deletions, and larger genomic rearrangements. Pathogenic variants are those that impair the normal function of the MSH6 protein, leading to a dysfunctional DNA mismatch repair system. The impact of a specific variant often depends on its location within the gene and how it alters the resulting protein product. Some variants may lead to a non-functional protein, while others might only partially affect its activity or stability [PMID:33671077].
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.-11863_457+1921del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-152)_457+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-152)_(*93_?)del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.-3097_457+2010del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.3557-?_(*93_?)del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.3953_3954ins32 | p.? | Pathogenic | ★★★☆ | Lynch syndrome |
c.1085del | p.Pro362fs | Pathogenic | ★★★☆ | Lynch syndrome |
c.1100A>G | p.His367Arg | Pathogenic | ★★★☆ | Lynch syndrome 1 |
c.1101del | p.His367fs | Pathogenic | ★★★☆ | Lynch syndrome |
c.1135_1139del | p.Arg378_Arg379insTer | 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 MSH6 gene are primarily associated with an increased susceptibility to inherited cancer syndromes. The most notable conditions linked to MSH6 variants include Lynch syndrome and constitutional mismatch repair deficiency (CMMRD).
CMMRD greatly increases an individual's cancer risk, often presenting at an early age. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer and cancer of the lining of the uterus. Individuals with Lynch syndrome also have an increased risk of cancers of the ovaries, stomach, and small intestine.
Inheritance pattern
Conditions caused by pathogenic MSH6 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 United Kingdom, the MSH6 gene is extensively evaluated within the NHS Genomic Medicine Service due to its significant clinical implications. It is featured on numerous panels within PanelApp UK, highlighting its importance in diagnosing and managing various conditions. MSH6 is categorised under 'Additional findings health related' and specific cancer susceptibility panels, including 'Adult solid tumours cancer susceptibility', 'Colorectal cancer pertinent cancer susceptibility', and 'Endometrial cancer pertinent cancer susceptibility'. It is also a key gene in the 'Inherited MMR deficiency (Lynch syndrome)' and 'Inherited polyposis and early onset colorectal cancer - germline testing' panels, among others, demonstrating its role in the assessment of inherited cancer risks across various organ systems.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with pathogenic MSH6 variants, adopting a healthy lifestyle is generally recommended, similar to general population guidelines. Research suggests that a balanced diet rich in fruits, vegetables, and whole grains, coupled with regular physical activity, may contribute to overall well-being. Maintaining a healthy body weight and avoiding smoking are also recognised as beneficial for cancer prevention in the general population. While these lifestyle choices are important for health, there is no conclusive evidence that they prevent cancer development specifically in individuals with MSH6-associated conditions.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent cancer or mitigate the effects of MSH6 pathogenic variants. While some research explores the potential roles of various vitamins and minerals in cancer prevention, these studies often involve the general population and do not specifically address individuals with inherited predispositions like those linked to MSH6. It is crucial for individuals considering any supplements to discuss this with a healthcare professional to ensure safety and appropriateness, as some supplements may interact with medications or have unintended effects.
Frequently asked questions
What is the primary function of the MSH6 gene?
The MSH6 gene provides instructions for making a protein that is a crucial component of the DNA mismatch repair system, responsible for identifying and correcting errors that occur during DNA replication.
How does MSH6 relate to cancer risk?
Pathogenic variants in the MSH6 gene impair the DNA mismatch repair process, leading to an accumulation of genetic mutations and significantly increasing the risk of developing various cancers, particularly those associated with Lynch syndrome.
What is Lynch syndrome?
Lynch syndrome is an inherited condition caused by pathogenic variants in mismatch repair genes, including MSH6. It significantly increases the lifetime risk of developing colorectal, endometrial, ovarian, and several other types of cancer.
What is constitutional mismatch repair deficiency (CMMRD) syndrome?
CMMRD is a severe, early-onset cancer predisposition syndrome resulting from biallelic pathogenic variants in mismatch repair genes like MSH6. It leads to a very high risk of various cancers starting in childhood.
Is MSH6 on any UK clinical genetic testing panels?
Yes, MSH6 is included on numerous NHS Genomic Medicine Service panels in the UK, such as those for adult solid tumours, colorectal cancer, endometrial cancer, and inherited MMR deficiency (Lynch syndrome).
Can lifestyle changes prevent MSH6-related cancers?
While a healthy lifestyle, including a balanced diet and regular exercise, is generally beneficial for overall health, there is no conclusive evidence that it can prevent cancer development specifically in individuals with MSH6 pathogenic variants. Regular medical surveillance is key.
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
- Schneider NB, Pastor T, Paula AE. Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. Cancer medicine. 2018. PMID: 29575718
- 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
- Edelbrock MA, Kaliyaperumal S, Williams KJ. Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities. Mutation research. 2013. PMID: 23391514
- Chhibber V, Dresser K, Mahalingam M. MSH-6: extending the reliability of immunohistochemistry as a screening tool in Muir-Torre syndrome. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2008. PMID: 18065960
- Peltomäki P. Lynch syndrome genes. Familial cancer. 2005. PMID: 16136382
- Cederquist K, Emanuelsson M, Göransson I. Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden. International journal of cancer. 2004. PMID: 14961575
- 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