A MET exon 14 skipping test identifies DNA or RNA changes that remove exon 14 from the MET messenger RNA and keep the MET growth receptor active longer than normal. This alteration occurs in about 3% to 4% of non-small cell lung cancers and is most often found in older adults with adenocarcinoma or sarcomatoid carcinoma, including people with little or no smoking history. A confirmed MET exon 14 skipping result can qualify a person with advanced lung cancer for selective MET inhibitors such as capmatinib or tepotinib. Testing is technically challenging because many different splice-site mutations, insertions, deletions, and larger changes can produce the same RNA event. DNA-only panels may miss some cases, while RNA testing directly shows exon skipping but can fail when RNA quality is poor. MET exon 14 skipping is distinct from MET amplification and MET protein overexpression. Results should state the exact alteration, method, specimen, tumor content, and whether functional skipping was demonstrated.
- MET exon 14 skipping is an actionable driver in roughly 3% to 4% of non-small cell lung cancers.
- RNA sequencing can directly detect exon 13-to-exon 15 joining and may find cases missed by DNA-only testing.
- A negative plasma result does not exclude MET exon 14 skipping because some lung cancers release little ctDNA.
- MET exon 14 skipping, MET amplification, and MET protein overexpression are separate biomarkers with different treatment evidence.
- Capmatinib and tepotinib are selective MET inhibitors used in defined advanced NSCLC settings, with edema as a common adverse effect.
Table of Contents
- What MET exon 14 skipping means
- Who should be tested
- DNA, RNA, tissue, and plasma testing
- How to read positive and negative results
- Targeted treatment and side effects
- Resistance and repeat testing
- Next steps and questions to ask
What MET exon 14 skipping means
MET encodes a receptor tyrosine kinase on the cell surface. Its normal ligand, hepatocyte growth factor, activates signaling through pathways that promote cell growth, movement, survival, and tissue repair. The cell must also turn MET off. Exon 14 encodes part of the juxtamembrane region containing tyrosine 1003, a binding site for the CBL protein. CBL helps tag MET for internalization and degradation.
When exon 14 is skipped, the CBL-binding region is lost. MET remains on the cell surface longer and sends prolonged growth signals. The tumor can become dependent on this pathway, creating a target for MET tyrosine kinase inhibitors.
MET exon 14 skipping is not one single mutation. Many different DNA changes can disrupt the splice donor, splice acceptor, branch point, polypyrimidine tract, or nearby regulatory sequences. They include substitutions, short insertions and deletions, and larger deletions that remove all or part of exon 14. The final functional event is the same: messenger RNA joins exon 13 directly to exon 15.
Reports may use terms such as:
- MET exon 14 skipping;
- METex14;
- MET exon 14 splice alteration;
- MET exon 14 deletion; or
- MET exon 13–15 junction detected.
“Exon 14 deletion” can be confusing because the DNA exon is not always deleted. In many cases, a small splice-site change causes the RNA to omit an intact exon. The report should identify whether the assay detected a DNA variant predicted to cause skipping or directly detected the skipped RNA transcript.
MET exon 14 skipping is seen mainly in non-small cell lung cancer. It occurs in adenocarcinoma and is enriched in pulmonary sarcomatoid carcinoma, but it can appear in other NSCLC histologies. It is generally an acquired tumor alteration, not an inherited mutation. Family members do not usually need testing for the tumor finding.
The alteration is usually mutually exclusive with dominant drivers such as classic EGFR mutations, ALK fusions, and ROS1 fusions, but rare co-alterations occur. TP53 and other co-mutations may influence biology and outcomes without changing the core definition of METex14-positive disease.
MET amplification is different. Amplification means extra copies of the MET gene. It can be a primary driver when copy number is very high or an acquired resistance mechanism after EGFR therapy. Low or intermediate copy gain may reflect broad chromosome gain rather than true MET dependence. MET protein overexpression by immunohistochemistry is also distinct and is not a reliable substitute for exon 14 testing.
A broad tumor molecular profiling test is preferred over a single MET test in advanced NSCLC because many other actionable drivers must be assessed at diagnosis. The panel should include both DNA and RNA when possible.
Who should be tested
Comprehensive molecular testing is recommended for people with advanced or metastatic nonsquamous NSCLC and for selected squamous cancers, particularly in never-smokers, younger patients, small biopsy specimens, or mixed histology. MET exon 14 should be part of that panel rather than ordered only after other genes are negative.
Testing is also important in pulmonary sarcomatoid carcinoma because the prevalence of METex14 is higher than in ordinary adenocarcinoma. These tumors can progress quickly, making timely molecular results especially valuable.
People with resected early-stage NSCLC may also undergo broad profiling, depending on local guidelines and access. The result can inform clinical trials and future treatment if the cancer recurs. However, selective MET inhibitors are primarily established for advanced disease. A positive result in a small, surgically removed tumor does not automatically mean targeted therapy should be given after surgery.
Clinical features cannot reliably select who has METex14. The alteration is more common in older adults and occurs in both smokers and never-smokers. Some tumors have high PD-L1 expression, but PD-L1 does not identify the driver. Molecular testing is required.
Testing should occur before first-line systemic therapy whenever advanced disease is diagnosed and the patient is clinically stable enough to wait for results. Starting immunotherapy before a driver profile is complete can complicate sequencing and expose a patient with a targetable alteration to unnecessary toxicity. Rapid plasma testing can help, but a negative plasma result needs tissue follow-up.
Retesting may be needed when:
- the original sample was too small or failed quality control;
- a DNA-only panel reported no driver and did not adequately assess splicing;
- the tumor progresses after a MET inhibitor;
- an old test had limited gene or exon coverage;
- the pathology changes or transformation is suspected; or
- MET amplification emerges as resistance to another targeted therapy.
A pathology review should confirm the diagnosis and tumor content before molecular testing. Lung biopsies can contain necrosis, inflammation, normal lung, or very few malignant cells. Cytology cell blocks, core biopsies, surgical tissue, and pleural-fluid cell blocks can all be suitable when properly processed.
Routine germline testing is not indicated for a typical tumor METex14 finding. Germline MET variants are associated with hereditary papillary renal cancer, but that syndrome involves activating kinase-domain variants rather than the usual lung-cancer splice alterations. A tumor report should not be used to diagnose hereditary kidney cancer.
DNA, RNA, tissue, and plasma testing
MET exon 14 is one of the best examples of why assay design matters. DNA testing looks for the many genomic variants that can disrupt splicing. RNA testing looks for the common functional product: an exon 13-to-exon 15 junction. Each approach has strengths and weaknesses.
DNA next-generation sequencing
DNA NGS can assess MET alongside mutations, copy number, and many other genes. It works well when the panel covers intronic regions flanking exon 14 and the bioinformatics pipeline recognizes splice-disrupting variants. Some assays sequence only coding exons and a few canonical splice bases, missing deep intronic changes or large deletions.
Not every nearby DNA variant causes skipping. A noncanonical change may need RNA confirmation or careful classification. The report should avoid calling a variant actionable solely because it lies near exon 14 without evidence that it disrupts splicing.
RNA testing
RNA NGS or reverse-transcription PCR directly detects the skipped transcript. It can capture different DNA mechanisms through one readout and improve detection of fusions and splice variants. In a large advanced-NSCLC cohort, adding RNA NGS to DNA NGS identified additional actionable structural variants, including more MET exon 14 cases.
RNA is fragile. Formalin fixation, old tissue, decalcification, heat, and low tumor content can degrade it. A failed RNA assay does not mean the tumor lacks skipping. DNA and RNA together provide the strongest coverage.
Tissue testing
Tissue remains the most complete specimen because it confirms histology and can support DNA, RNA, PD-L1, and other analyses. The pathologist selects a tumor-rich area and may use macrodissection. A tiny biopsy must be managed carefully so repeated single-gene tests do not exhaust the material.
The report should state tumor percentage and quality limitations. A negative result from a sample with 5% tumor is less reassuring than a negative result from a well-covered sample with 50% tumor.
Plasma liquid biopsy
Plasma NGS analyzes circulating tumor DNA and can return results quickly without another invasive biopsy. It can detect splice-site variants and other drivers, but sensitivity depends on tumor shedding and panel design. Larger or more widespread tumors, especially with liver or bone metastases, tend to release more ctDNA.
A positive plasma METex14 result can be clinically useful when the variant is clearly pathogenic and fits NSCLC. A negative result does not exclude the alteration. In the VISION study, some tissue-positive patients were plasma-negative and still had durable benefit from tepotinib. Plasma negativity often reflected low ctDNA burden rather than absence of the driver.
When plasma is negative and tissue is available, tissue DNA plus RNA should follow. When tissue is unsafe to obtain, repeating plasma during clear progression may increase yield, but treatment should not be delayed indefinitely.
Other methods
Focused PCR assays can detect the exon 13–15 RNA junction quickly. Sanger sequencing may identify a known splice-site variant but is less sensitive and less comprehensive. Immunohistochemistry for MET protein cannot replace molecular testing. Fluorescence in situ hybridization measures amplification, not exon skipping.
A high-quality report includes the exact DNA or RNA finding, specimen, method, limit of detection, tumor fraction, and whether MET amplification was also assessed. It should clearly separate confirmed skipping from a variant of uncertain splice effect.
How to read positive and negative results
A positive result means a pathogenic splice alteration or the skipped RNA transcript was detected. In advanced NSCLC, this is an actionable oncogenic driver. The report may list a DNA change such as a splice donor mutation or a deletion around exon 14. Different DNA variants can carry the same treatment implication when they are proven to cause skipping.
The variant allele fraction, or VAF, does not measure the percentage of the tumor that is MET-dependent. In tissue, VAF reflects tumor purity, copy number, and clonality. In plasma, it reflects ctDNA shedding and the amount of normal cell-free DNA. A low-VAF but well-validated splice alteration can still be actionable.
A positive result should be distinguished from:
| MET finding | What it means | Established interpretation |
|---|---|---|
| Exon 14 skipping | Loss of juxtamembrane degradation site | Strong target for selective MET inhibitors in advanced NSCLC |
| High-level MET amplification | Many extra MET copies | Can be a driver or resistance mechanism; thresholds and treatment evidence differ |
| Low-level copy gain | Modest increase, sometimes whole-chromosome gain | Often less predictive of MET dependence |
| MET protein overexpression | Increased staining by IHC | Not equivalent to METex14 and not sufficient alone for the same therapy |
| MET VUS | Uncertain sequence change | Should not guide treatment without evidence of activation or skipping |
A negative result means no reportable METex14 event was found within the assay’s limits. Review whether the test included RNA, covered intronic splice regions, had sufficient tumor, and passed quality control. A negative DNA-only hotspot panel may not be definitive.
Reasons for a false-negative result include:
- low tumor percentage;
- degraded RNA;
- a splice variant outside the captured region;
- a large deletion not detected by the pipeline;
- a noncanonical variant not recognized as pathogenic;
- low plasma shedding; or
- treatment reducing tumor DNA.
An indeterminate result is not negative. Examples include failed RNA quality, insufficient DNA, or a possible splice variant with uncertain functional effect. The next step may be repeat testing, an orthogonal assay, or a new specimen.
Tissue and plasma can disagree. Tissue-positive/plasma-negative cases are expected when shedding is low. Plasma-positive/tissue-negative cases can reflect tumor heterogeneity, a more recent clone, or inadequate tissue. Because METex14 is a strong driver, a credible plasma-positive result should be reviewed promptly rather than dismissed.
A variant of uncertain significance near exon 14 should not automatically qualify for targeted therapy. RNA evidence, splicing prediction, prior observations, and functional data can support reclassification. When treatment depends on the call, molecular pathology consultation is useful.
METex14 can coexist with MET amplification. Amplification may increase pathway signaling and can emerge during progression. The report should state both findings separately because they may affect biology and resistance.
Targeted treatment and side effects
Capmatinib and tepotinib are oral, selective type Ib MET inhibitors with established activity in advanced NSCLC containing MET exon 14 skipping. They bind the active MET kinase and can produce tumor shrinkage in both previously treated and treatment-naive patients. Activity has also been observed in some patients with brain metastases.
The exact treatment line and approval language differ by country and are updated over time. Some guidelines favor a selective MET inhibitor as a preferred option for advanced METex14-positive disease. Others integrate it with chemotherapy or immunotherapy based on access, symptoms, prior therapy, and patient factors. Current local guidance should be checked rather than relying on an old report.
Capmatinib was studied in the GEOMETRY mono-1 trial, and tepotinib in the VISION trial. Both showed meaningful and durable responses. Cross-trial comparisons should be avoided because eligibility, prior treatment, assessment, and follow-up differed.
Common adverse effects include:
- peripheral edema, often in the legs;
- nausea, reduced appetite, vomiting, or diarrhea;
- fatigue;
- increased blood creatinine;
- low albumin;
- liver enzyme elevation; and
- shortness of breath.
Edema is especially common and can become dose-limiting. Management can include compression, leg elevation, activity, dietary review, assessment for heart, kidney, liver, or venous disease, dose interruption, and dose reduction. Diuretics may help selected patients but do not correct all MET-inhibitor edema and can cause dehydration or electrolyte problems.
Serum creatinine can rise because MET inhibitors reduce tubular secretion of creatinine, not necessarily because true kidney filtration has worsened. Clinicians may use cystatin C or other measures when the change is unexpected. Kidney function still requires careful assessment because genuine injury can also occur.
Interstitial lung disease or pneumonitis is uncommon but serious. New or worsening cough, fever, or shortness of breath requires prompt evaluation and drug interruption until the cause is clear. Liver tests should be checked regularly, especially early in treatment.
Drug interactions matter. Capmatinib and tepotinib have different metabolism and transporter effects. The oncology pharmacist should review prescription drugs, over-the-counter medicines, and supplements. Dose changes should be made by the treating team, not by the patient.
Immunotherapy can work in some METex14-positive cancers, but high PD-L1 does not guarantee benefit. Driver-positive lung cancers can have less predictable response to single-agent immunotherapy, particularly in never-smokers. Treatment sequencing should consider the availability of a MET inhibitor and the potential for overlapping toxicity after immunotherapy.
For early-stage disease, surgery, radiation, and standard perioperative therapy remain the foundation. A METex14 result may qualify a patient for a clinical trial, but routine adjuvant MET inhibition is not established in the same way as treatment for advanced disease.
Resistance and repeat testing
Most advanced cancers eventually develop resistance. MET-dependent, or on-target, resistance can arise through secondary mutations in the kinase domain. Changes at residues D1228 or Y1230 can reduce binding of type I MET inhibitors such as capmatinib and tepotinib. Other resistance occurs outside MET through activation of KRAS, BRAF, EGFR, HER3, PI3K, or other pathways.
Resistance may be heterogeneous. One metastasis can carry a MET kinase mutation while another activates a bypass pathway. Plasma NGS can sample several sites and detect multiple clones, while tissue can reveal histologic transformation and provide RNA or protein information.
At progression, the team may consider:
- confirming true progression with imaging and symptoms;
- continuing the MET inhibitor with local treatment for limited oligoprogression;
- tissue biopsy of a progressing site;
- plasma profiling for acquired alterations;
- switching to chemotherapy or another standard therapy; or
- enrolling in a trial of a next-generation MET inhibitor or combination.
Type II MET inhibitors bind a different inactive conformation and may retain activity against some resistance mutations, but clinical evidence is still developing. No resistance result should be assumed to identify an effective drug without current trial or guideline support.
MET amplification can also appear as an acquired resistance mechanism in EGFR-mutant lung cancer. That setting is biologically different from de novo MET exon 14 skipping. Treatment may require combined EGFR and MET inhibition in a trial or approved regimen rather than MET monotherapy.
A repeat positive METex14 result does not mean the original drug must continue indefinitely. The driver can remain present while a second alteration causes resistance. Conversely, failure to detect METex14 in plasma at progression may reflect low shedding rather than loss of the driver.
Serial VAF can roughly track tumor burden, but routine treatment decisions should not rely on a single molecular percentage. Imaging, symptoms, organ function, and clinical trajectory remain primary. A transient rise after treatment or local therapy can occur.
When a tumor progresses only in the brain, plasma may stay negative. Brain MRI and, in selected cases, cerebrospinal-fluid testing are more informative. Drug penetration into the central nervous system and local treatment options should be reviewed.
The best time to repeat testing is when the result could change management. Repeating the same limited assay without a plan adds little. A broad tissue and plasma approach is more useful when resistance mechanisms are diverse.
Next steps and questions to ask
After a positive result, confirm that the diagnosis is NSCLC, the alteration truly causes exon 14 skipping, and the patient’s stage and treatment setting match the evidence for a MET inhibitor. Review brain imaging, symptoms, performance status, organ function, other mutations, and PD-L1.
Ask the oncology team:
- Was skipping detected directly in RNA or inferred from a DNA splice variant?
- Did the assay include both DNA and RNA, and what was the sample’s tumor content?
- Is MET amplification also present, and how was it measured?
- Is capmatinib or tepotinib preferred in this setting, and why?
- What edema, liver, lung, kidney, and drug-interaction monitoring is planned?
- Should baseline brain MRI be performed?
- What is the plan if only one or two sites progress?
- Will tissue or plasma profiling be repeated at broader progression?
After a negative result, ask whether the test was technically capable of detecting diverse MET splice changes. If the panel was DNA-only, limited to coding exons, or performed on scant tissue, RNA testing may be appropriate. A negative plasma test should not end the search for a driver when tissue can be tested.
After an uncertain splice result, request molecular pathology review. The team can look for an exon 13–15 RNA junction, use another assay, or test a different block. High-stakes treatment should not rest on an unsupported prediction.
During treatment, track weight, leg swelling, breathing, liver tests, kidney markers, albumin, and medication changes. Sudden one-sided leg swelling or chest pain needs urgent evaluation for a clot rather than being assumed to be ordinary drug edema. New shortness of breath can represent pneumonitis, infection, embolism, heart disease, pleural fluid, or cancer progression.
Keep a copy of the full molecular report, not just a clinic note saying “MET positive.” The exact finding matters because METex14, amplification, and overexpression have different meanings. Also record whether the result came from tissue or plasma and whether it was collected before or after therapy.
Family members do not need testing for an ordinary tumor MET exon 14 alteration. If the report unexpectedly suggests a germline MET kinase variant or there is a family history of papillary kidney cancer, genetics evaluation can determine whether separate inherited testing is appropriate.
MET exon 14 testing is most valuable when it is built into comprehensive profiling, uses methods that can capture diverse splice events, and returns before treatment begins. A precise result can turn an uncommon lung-cancer driver into a practical treatment option while preventing MET amplification or protein staining from being mistaken for the same biomarker.
References
- Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial 2024 (Clinical Trial)
- Tepotinib Treatment in Patients With MET Exon 14-Skipping Non-Small Cell Lung Cancer: Long-term Follow-up of the VISION Phase 2 Nonrandomized Clinical Trial 2023 (Clinical Trial)
- Tepotinib in patients with MET exon 14 skipping non-small cell lung cancer 2025 (Review)
- Liquid and Tissue Biopsies for Identifying MET Exon 14 Skipping NSCLC: Analyses from the Phase II VISION Study of Tepotinib 2025 (Clinical Trial)
- Actionable Structural Variant Detection via RNA-NGS and DNA-NGS in Patients With Advanced Non-Small Cell Lung Cancer 2024 (Cohort Study)
- MET alterations in advanced non-small cell lung cancer 2024 (Review)
Disclaimer
This article is educational and does not replace molecular pathology review or treatment planning by a thoracic oncology team. MET exon 14 results must be interpreted by assay method, specimen quality, cancer stage, and current approvals; MET amplification and protein overexpression are not interchangeable with exon skipping. New shortness of breath, chest pain, severe swelling, jaundice, or other serious symptoms during treatment require prompt medical evaluation.
