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MET
MET proto-oncogene, receptor tyrosine kinase
The MET gene provides instructions for making a protein involved in essential cellular processes, including cell growth, movement, and survival, acting as a proto-oncogene. The MET gene is a proto-oncogene that plays a critical role in early development and tissue regeneration.
MET is located on the long (q) arm of chromosome 7, at band 7q31.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The MET gene, scientifically known as MET proto-oncogene, receptor tyrosine kinase, is fundamental for cellular communication and regulation. It contains the genetic information for a protein that serves as a cell-surface receptor. This receptor typically binds to a specific growth factor, initiating a signal cascade inside the cell essential for numerous biological functions.
Changes or errors within the MET gene can disrupt these normal cellular activities, potentially leading to uncontrolled cell proliferation and division. As a proto-oncogene, MET supports healthy growth and development, but genetic alterations can transform it into an oncogene, promoting tumour formation. Therefore, understanding the MET gene's function is critical for comprehending the development of certain inherited conditions and cancers.
What the gene does
The MET gene encodes a receptor tyrosine kinase, commonly known as the MET protein or hepatocyte growth factor receptor (HGFR). This protein is located on the cell surface, crucial for transmitting extracellular signals into the cell's interior. Its main role involves binding to hepatocyte growth factor (HGF), a molecule that stimulates cell growth, movement, and shape changes.
Upon HGF binding, the MET receptor undergoes a change in its structure and becomes active, a process called autophosphorylation. This phosphorylation creates binding sites for various intracellular signalling proteins, initiating a complex web of pathways vital for cell survival, proliferation, dispersion, and invasion. These pathways are integral to normal embryonic development, organ formation, and wound healing. When MET signalling is dysregulated, often due to specific genetic variants, it can lead to uncontrolled cell growth and tumour development by continuously activating these pathways, even without HGF.
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Chromosome location
The MET gene resides on the long arm (q) of chromosome 7, specifically at band 7q31.2. This alphanumeric designation precisely locates its position within the human genome, enabling accurate identification during genetic analyses. Any genetic variations or errors within the MET gene will be found at this specific chromosomal site.
Protein structure
The MET protein is a transmembrane receptor consisting of 1390 amino acids. It has several distinct structural regions, each contributing to its overall role. The extracellular part includes a large Sema domain, spanning amino acids 27-515, which is primarily responsible for binding to its ligand, hepatocyte growth factor. Following this are three IPT/TIG domains: IPT/TIG 1 (amino acids 563-655), IPT/TIG 2 (amino acids 657-739), and IPT/TIG 3 (amino acids 742-836), which are important for correct protein folding and interactions.
The intracellular section of the MET protein contains the Protein kinase domain, located from amino acids 1078-1345. This domain is essential for the protein's enzymatic activity, specifically its tyrosine kinase function. This involves adding phosphate groups to other proteins, which initiates cellular signalling cascades. Additionally, specific regions have been identified that interact with other proteins: an Interaction with RANBP9 region (amino acids 1212-1390) and an Interaction with MUC20 region (amino acids 1320-1359), highlighting its complex role in cellular networks.
Key variants
Genetic changes within the MET gene can range from single nucleotide alterations to larger deletions or duplications. These genetic variants can affect the MET protein's function in various ways, such as making the protein overactive, reducing its responsiveness to regulatory signals, or preventing its proper formation. Depending on their nature and location, MET gene variants are classified as pathogenic, likely pathogenic, or variants of uncertain significance, reflecting their potential health impact. The inheritance pattern for conditions linked to MET is generally autosomal dominant (AD), meaning that inheriting one altered copy of the gene is sufficient to increase a person's predisposition to a condition.
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.3274G>A | p.Val1092Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Renal cell carcinoma |
c.3281A>G | p.His1094Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Papillary renal cell carcinoma type 1 |
c.3392T>C | p.Met1131Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary papillary renal cell carcinoma |
c.3658G>A | p.Val1220Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Renal cell carcinoma |
c.2521T>G | p.Phe841Val | Pathogenic | ★☆☆☆ | Autosomal Recessive Nonsyndromic Hearing Loss and Deafness |
c.2855del | p.Phe952fs | Pathogenic | - | Colorectal cancer |
c.3562G>T | p.Val1188Leu | Pathogenic | - | Papillary renal cell carcinoma type 1 |
c.3682G>A | p.Asp1228Asn | Pathogenic | - | Papillary renal cell carcinoma type 1 |
c.3701A>G | p.Tyr1234Cys | Pathogenic; risk factor | - | Arthrogryposis, distal, type 1A |
c.3731A>G | p.Lys1244Arg | Pathogenic | - | Pediatric hepatocellular carcinoma |
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
Variants in the MET gene are associated with an increased predisposition to certain inherited conditions, notably within the category of cancer predispositions. One such condition linked to MET gene variants is Hereditary papillary RCC. This condition follows an autosomal dominant inheritance pattern, meaning that inheriting a single altered copy of the MET gene can elevate an individual's risk. Understanding specific variants and their effects is crucial for assessing risk and informing clinical management.
Inheritance pattern
Conditions caused by pathogenic MET variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The MET gene is recognised within the UK's NHS Genomic Medicine Service, indicating its clinical importance for particular conditions. It is classified as 'green' on several NHS Genomic Test Panels, signifying sufficient evidence for its routine use in diagnostic testing. These panels include 'Adult solid tumours cancer susceptibility', 'Adult solid tumours for rare disease', 'Arthrogryposis' (under panel R83), 'Inherited renal cancer' (under panel R224), and 'Renal cancer pertinent cancer susceptibility', reflecting its relevance in various cancer and rare disease contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Adopting a healthy lifestyle is widely recommended for general well-being and may offer supportive benefits for individuals susceptible to certain conditions. However, there is no conclusive evidence that specific lifestyle interventions can prevent conditions associated with MET gene variants. General guidance includes consuming a balanced diet rich in fruits, vegetables, and whole grains, maintaining a healthy weight, and engaging in regular physical activity. Avoiding smoking and limiting alcohol intake also contribute to overall health. These practices support cellular function and may help reduce the risk of various diseases in the general population.
Supplement considerations
Currently, there is no conclusive scientific evidence indicating that specific dietary supplements can prevent, treat, or lessen the effects of conditions associated with MET gene variants. Individuals considering supplements should exercise caution and discuss with a healthcare professional before taking any. A balanced diet typically provides the necessary nutrients for most people, and excessive supplementation can sometimes lead to adverse effects.
Frequently asked questions
What is the MET gene?
The MET gene provides instructions for making the MET protein, a receptor tyrosine kinase located on the surface of cells. It plays a critical role in processes like cell growth, movement, and survival by responding to growth factors.
What conditions are associated with the MET gene?
Variants in the MET gene are associated with an increased predisposition to certain inherited conditions, including Hereditary papillary RCC, which is a type of kidney cancer.
How is the MET gene related to cancer?
MET is classified as a proto-oncogene. While essential for normal cell functions, certain genetic variants can cause it to become overactive or dysregulated, acting as an oncogene that promotes uncontrolled cell growth and tumour development.
What does it mean if MET is 'green' on an NHS Genomic Test Panel?
A 'green' status on an NHS Genomic Test Panel indicates that there is strong evidence for the gene's association with a particular condition, and it is routinely used in diagnostic genetic testing within the NHS.
Is Hereditary papillary RCC inherited?
Yes, Hereditary papillary RCC associated with MET gene variants is typically inherited in an autosomal dominant manner. This means that inheriting just one copy of the altered MET gene is sufficient to increase an individual's risk for the condition.