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MSH2
mutS homolog 2
The MSH2 gene provides instructions for a protein that is essential for DNA mismatch repair, a critical process for maintaining genomic stability and preventing cancer. MSH2 plays a vital role in correcting errors that occur during DNA replication, acting as part of a complex that identifies and repairs mismatched DNA segments.
MSH2 is located on the short (p) arm of chromosome 2, at band 2p21-p16.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The MSH2 gene, also known as mutS homolog 2, is a key component of the DNA mismatch repair (MMR) system in human cells. This system is responsible for identifying and correcting specific types of errors that arise during DNA replication, such as base-base mismatches and small insertion-deletion loops [PMID:33671239]. Accurate DNA replication is fundamental for maintaining the integrity of the genome and preventing uncontrolled cell growth. Inherited pathogenic variants in the MSH2 gene significantly impair this repair mechanism, leading to an increased susceptibility to various cancers. The MSH2 gene is classified as an ACMG SF v3.2 Tier 1 gene, meaning variants in it are considered to have strong evidence of pathogenicity and clinical actionability [PMID:34289498].
What the gene does
The MSH2 gene provides instructions for synthesising the MSH2 protein, which is an integral part of the DNA mismatch repair (MMR) pathway. This pathway acts as a crucial surveillance mechanism during DNA replication, preventing the accumulation of genetic errors that could lead to mutations and potentially cancer. The MSH2 protein typically forms a heterodimer with either the MSH6 protein (forming the MutSalpha complex) or the MSH3 protein (forming the MutSbeta complex) [PMID:33671239].
During DNA replication, errors can occur where incorrect nucleotide bases are incorporated or small segments are missed or duplicated. The MSH2-containing protein complexes are responsible for recognising these specific types of errors, particularly base-base mismatches and small insertion-deletion loops. Once a mismatch is detected, the MutSalpha or MutSbeta complex binds to the aberrant DNA segment, acting as a molecular flag. This binding then recruits other proteins involved in the MMR pathway, such as MLH1 and PMS2, to form a larger repair complex [PMID:32252119].
The subsequent steps involve excising the erroneous DNA strand and then synthesising a new, corrected strand using the intact complementary strand as a template. This precise process ensures that the genetic information passed on to daughter cells is accurate. Pathogenic variants in MSH2 can compromise its ability to form functional complexes or recognise DNA mismatches, thereby leading to a defective MMR system. This deficiency results in an increased rate of spontaneous mutations throughout the genome, a characteristic often observed in MSH2-related cancers.
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Chromosome location
The MSH2 gene is located on the short arm of chromosome 2, specifically within the region designated 2p21-p16.3. This chromosomal location indicates that the gene resides on the second human chromosome, towards the p (petite) arm. The MSH2 gene itself spans a significant length of DNA, comprising a number of exons that are transcribed and translated to produce the MSH2 protein. Its precise position within this band can be further detailed, contributing to its unique genetic signature. The MSH2 protein, once translated, consists of 934 amino acids.
Protein structure
The MSH2 protein is composed of 934 amino acids and exhibits a modular structure critical for its function in DNA mismatch repair. A notable functional region identified within the MSH2 protein is involved in its interaction with EXO1, specifically located between amino acids 601 and 671. This interaction is important for coordinating the excision step of the mismatch repair pathway, where EXO1 (Exonuclease 1) removes the mispaired DNA segment. The MSH2 protein also contains domains responsible for ATPase activity and dimerisation, allowing it to bind to other proteins like MSH6 or MSH3 to form functional MutS complexes. These complexes then recognise and bind to DNA mismatches, initiating the repair process.
Key variants
Genetic variants within the MSH2 gene can impact its normal function, ranging from benign changes with no observable effect to pathogenic variants that significantly impair the gene's protein product. These pathogenic variants often lead to a dysfunctional DNA mismatch repair system. The types of variants encountered in MSH2 include point mutations, which alter a single nucleotide, as well as larger deletions or insertions that can disrupt the gene's coding sequence or regulatory regions. The specific location and nature of a variant dictate its potential clinical impact. Understanding the landscape of MSH2 variants is crucial for genetic counselling and risk assessment, particularly given its role in inherited cancer predisposition syndromes.
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.-1753_645+922del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.-4729_367-353del | - | Pathogenic | ★★★☆ | Lynch syndrome 1 |
c.(?_-68)_1276+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-68)_1386+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-68)_1661+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-68)_1759+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-68)_211+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-68)_2634+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.-823_1076+5984del | - | Pathogenic | ★★★☆ | Lynch syndrome 1 |
c.-956_1077-5607del | - | 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 MSH2 gene are primarily associated with an increased risk of developing inherited cancer predisposition syndromes. The two main conditions linked to MSH2 are Lynch syndrome and constitutional mismatch repair deficiency (CMMRD). Individuals with MSH2-related Lynch syndrome have a substantially elevated lifetime risk of various cancers, particularly colorectal and endometrial cancers, but also ovarian, gastric, small intestine, urinary tract, and brain cancers. Constitutional mismatch repair deficiency (CMMRD) is a rare, severe autosomal recessive condition typically caused by biallelic pathogenic variants in MMR genes, including MSH2, leading to very early-onset childhood cancers affecting multiple organs.
Inheritance pattern
Conditions caused by pathogenic MSH2 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, the MSH2 gene is extensively recognised within the NHS Genomic Medicine Service, featuring across numerous PanelApp panels. Its inclusion highlights its clinical significance in diagnosing and managing various inherited conditions and cancer susceptibilities. MSH2 is listed as 'green' in panels such as 'Inherited MMR deficiency (Lynch syndrome)', 'Adult solid tumours cancer susceptibility', and 'Childhood solid tumours cancer susceptibility', among many others. This widespread inclusion indicates that MSH2 is routinely analysed in clinical genomic testing for individuals suspected of having hereditary cancer syndromes or certain rare diseases, affirming its established role in clinical diagnostics.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with MSH2 pathogenic variants, particularly those associated with Lynch syndrome, lifestyle choices can play a supportive role in overall health management, although they do not prevent the genetic predisposition. Research suggests that maintaining a healthy body weight through balanced nutrition and regular physical activity may contribute to a reduced risk of colorectal cancer in the general population, a benefit that might extend to individuals with Lynch syndrome [PMID:31548324]. A diet rich in fruits, vegetables, and whole grains, and low in red and processed meats, is generally recommended for its broader health benefits and has been associated with a lower risk of several cancer types [PMID:31548324]. Furthermore, avoiding smoking and limiting alcohol intake are important general cancer prevention strategies that apply to everyone, including those with a genetic predisposition to cancer. These lifestyle measures are considered complementary to clinical surveillance and early detection programmes.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific supplements can prevent cancer development in individuals with MSH2 pathogenic variants or those with Lynch syndrome. While some research explores the potential role of certain vitamins or minerals in cancer prevention in the general population, these findings cannot be directly applied to individuals with a genetic predisposition without specific clinical studies. For instance, some studies have investigated the impact of aspirin on colorectal cancer risk in Lynch syndrome, but this is a medication, not a supplement, and any use should be under strict medical supervision and discussion with a healthcare provider [PMID:30612711]. Any individual considering taking supplements should first discuss this with their healthcare provider to ensure it is safe and appropriate, as supplements can interact with medications or have unintended effects.
Frequently asked questions
What is the primary function of the MSH2 gene?
The MSH2 gene provides instructions for making a protein that is essential for DNA mismatch repair, a critical cellular process that corrects errors made during DNA replication to maintain genetic stability.
What conditions are associated with pathogenic MSH2 variants?
Pathogenic variants in the MSH2 gene are primarily associated with Lynch syndrome, which increases the risk of various cancers, and constitutional mismatch repair deficiency (CMMRD), a severe early-onset cancer syndrome.
How is MSH2-related Lynch syndrome inherited?
Lynch syndrome caused by MSH2 pathogenic variants is inherited in an autosomal dominant pattern. This means an individual needs to inherit only one copy of the pathogenic variant from either parent to be at an increased risk.
Can lifestyle changes prevent cancer in individuals with MSH2 variants?
While lifestyle changes such as a healthy diet and regular exercise may generally reduce cancer risk, they do not prevent the genetic predisposition caused by MSH2 variants. They are complementary to clinical surveillance.
Is the MSH2 gene included in NHS genomic testing?
Yes, the MSH2 gene is extensively included in numerous NHS PanelApp panels, indicating its importance in clinical genomic testing for hereditary cancer syndromes and rare diseases in the UK.
What is constitutional mismatch repair deficiency (CMMRD)?
CMMRD is a rare and severe inherited disorder caused by inheriting two pathogenic variants in MMR genes, including MSH2. It leads to a very high risk of various cancers developing in early childhood.
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
- Arshita N, Lestari RV, Hutajulu SH. The Tendency of Having MSH2 and MSH6 Microsatellite Instability among Clinicopathological Features in Patients with Colorectal Cancer. Asian Pacific journal of cancer prevention : APJCP. 2018. PMID: 30486602
- 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
- South CD, Hampel H, Comeras I. The frequency of Muir-Torre syndrome among Lynch syndrome families. Journal of the National Cancer Institute. 2008. PMID: 18270343
- Lützen A, de Wind N, Georgijevic D. Functional analysis of HNPCC-related missense mutations in MSH2. Mutation research. 2008. PMID: 18822302
- Rishi K, Font RL. Sebaceous gland tumors of the eyelids and conjunctiva in the Muir-Torre syndrome: a clinicopathologic study of five cases and literature review. Ophthalmic plastic and reconstructive surgery. 2004. PMID: 14752307
- Guillem JG, Moore HG, Palmer C. A636P testing in Ashkenazi Jews. Familial cancer. 2004. PMID: 15516845
- 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