About MET
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MET c.226G>A, p.(Glu76Lys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present in gnomAD v4.1 at an extremely low allele frequency (1/1,614,028 alleles, AF = 6.2e-7, ~0.00006%), well below the <0.1% PM2 threshold for a rare variant with no population data support.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict a benign impact: REVEL score 0.097 (benign, well below ~0.5 threshold), BayesDel score -0.574 (benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). Consistent benign prediction across independent in silico tools supports BP4 at supporting strength.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,614,028 alleles
gnomAD v4.1: 1 / 1,614,028 alleles. Recorded AF 6.19568e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MET, a receptor tyrosine kinase, is recurrently altered by mutation or amplification in various cancer types.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV100577327, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is extremely rare in population databases (1/1,614,028 gnomAD v4.1 alleles; absent from gnomAD v2.1 and gnomAD-Canada), satisfying PM2 at supporting strength.
Multiple lines of computational evidence consistently predict a benign effect (REVEL 0.097, BayesDel -0.574, SpliceAI max delta 0.00), satisfying BP4 at supporting strength.
No functional data, de novo events, co-segregation, case-control data, or variant-specific publications were identified. The variant is absent from ClinVar and has been observed once in COSMIC as a somatic finding.
One pathogenic supporting criterion (PM2) and one benign supporting criterion (BP4) are present, resulting in a classification of Uncertain Significance per generic ACMG/AMP 2015 combination rules (PMID:25741868).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada, and present in gnomAD v4.1 at an extremely low allele frequency (1/1,614,028 alleles, AF = 6.2e-7, ~0.00006%), well below the <0.1% PM2 threshold for a rare variant with no population data support. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD-Canada v1.0
- gnomAD v4.1: 1/1
- 614
- 028 alleles (AF=6.2e-7
- 0 homozygotes)
Sources
BP4 SupportingMultiple lines of computational evidence predict a benign impact: REVEL score 0.097 (benign, well below ~0.5 threshold), BayesDel score -0.574 (benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). Consistent benign prediction across independent in silico tools supports BP4 at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.097 (benign)
- BayesDel: -0.574 (benign)
- SpliceAI: max delta 0.00
- no splicing effect predicted
- HCI Prior: not available for MET
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No different nucleotide change at codon 76 resulting in the same amino acid substitution (Glu76Lys) has been identified and classified as pathogenic. This variant is absent from ClinVar, and no literature describes an alternate nucleotide change causing the same missense. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no pathogenic same-amino-acid comparators identified
Sources
PS2 No de novo occurrence data is available for NM_001127500.3:c.226G>A. No publications report this variant as a confirmed de novo event in a patient with relevant disease and no family history. Details ▾Hide ▴
Evidence considered
- No de novo data identified in ClinVar
- literature
- or evidence sources
Still missing
- De novo status cannot be determined without parental testing or published de novo reports
PS3 No functional data exists for NM_001127500.3:c.226G>A (p.E76K). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications containing this variant were identified through literature search. REVEL (0.097) and BayesDel (-0.574) are computational predictors, not functional studies, and predict a benign effect. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
- REVEL score 0.097 (benign)
- BayesDel score -0.574 (benign)
Still missing
- No experimental functional studies available for this variant
Sources
PS4 No case-control, cohort, or case series data demonstrate enrichment of this variant in affected individuals compared to controls. The variant has been observed only once in gnomAD v4.1 (1/1,614,028 alleles) and is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant observed in 1/1
- 614
- 028 gnomAD v4.1 alleles
- Variant absent from ClinVar (no patient submissions)
Still missing
- No case-control or cohort data to establish prevalence in affected individuals
Sources
PM1 Position Glu76 is in the SEMA domain of MET, but this residue is not a statistically significant mutational hotspot per CancerHotspots.org. No CSPEC/VCEP framework defines this residue or domain region as a pathogenic hotspot for MET. Domain-level inference from sparse testing does not satisfy PM1 in the absence of hotspot data or VCEP designation. Details ▾Hide ▴
Evidence considered
- CancerHotspots.org: residue E76 not in a statistically significant hotspot
- OncoKB: Unknown Oncogenic Effect at this position
- No CSPEC/VCEP framework identifies the SEMA domain position 76 as a critical hotspot
Sources
PM6 No de novo data is available for this variant. PM6 requires an assumed de novo occurrence (maternity and paternity not confirmed) in a patient with disease and no family history. Details ▾Hide ▴
Evidence considered
- No de novo data identified in any evidence source
Still missing
- De novo status cannot be assessed without parental data
PP1 No co-segregation data is available for this variant. No family studies have been performed or reported. Details ▾Hide ▴
Evidence considered
- No co-segregation data in ClinVar
- literature
- or other evidence sources
Still missing
- Co-segregation cannot be assessed without family studies
PP2 While MET is a gene where missense variants can be pathogenic (particularly in the kinase domain for hereditary papillary renal cell carcinoma), the variant's position in the SEMA domain and its consistently benign in silico predictions (REVEL 0.097, BayesDel -0.574) do not support a pathogenic interpretation for PP2. The computational evidence uniformly points toward a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.097 (benign)
- BayesDel -0.574 (benign)
- Variant is in the SEMA domain
- not the kinase domain hotspot
Sources
revelbayesdel
PP3 Multiple lines of in silico evidence predict a benign effect: REVEL score 0.097 (benign, well below the ~0.5 pathogenic threshold), BayesDel score -0.574 (benign-leaning), and SpliceAI max delta 0.00 (no predicted splice impact). These scores do not support a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.097 (benign)
- BayesDel: -0.574 (benign)
- SpliceAI: max delta 0.00 (no splice effect)
Sources
PP4 No specific patient phenotype or family history data is available for assessment. PP4 requires that the patient's phenotype or family history is highly specific for the disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No patient phenotype or family history data available in the case materials
Still missing
- Patient phenotype and family history information not provided in case materials
PP5 This variant is absent from ClinVar. No reputable source (clinical diagnostic laboratory, expert panel) has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source classification available
Sources
BA1 The variant allele frequency in gnomAD v4.1 (AF = 6.2e-7, ~0.00006%) is far below the >1% threshold for BA1. This criterion is not satisfied. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 6.2e-7 (1/1
- 614
- 028 alleles)
- well below 1% BA1 threshold
Sources
BS1 The variant allele frequency (AF = 6.2e-7, ~0.00006%) is well below the >0.3% BS1 threshold for a rare variant. The single observation in 1.6 million alleles does not support BS1. Details ▾Hide ▴
BS2 No evidence that this variant has been observed in a healthy adult individual in a manner that satisfies BS2 (e.g., homozygous or in trans with a pathogenic variant). The single gnomAD v4.1 observation lacks phenotype data. Details ▾Hide ▴
Evidence considered
- Single gnomAD observation with no phenotype data available
Still missing
- Cannot confirm the phenotype of the single gnomAD observation
Sources
BS3 No well-established functional studies demonstrate a neutral effect for this variant. Computational predictors (REVEL 0.097, BayesDel -0.574) are in silico tools, not experimental functional assays. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. Details ▾Hide ▴
Evidence considered
- REVEL 0.097 and BayesDel -0.574 are computational predictions
- not functional studies
- No experimental functional data identified for this variant
Still missing
- No experimental functional studies available to assess neutral effect
Sources
revelbayesdel
BS4 No segregation data is available. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Family segregation data not available
BP1 MET disease mechanisms include both truncating variants (exon 14 skipping in various cancers) and missense variants (kinase domain activating mutations in hereditary papillary renal cell carcinoma). Missense variants are a recognized disease mechanism for MET-associated conditions; therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
- MET missense variants cause hereditary papillary RCC (kinase domain)
- MET truncating variants cause disease via exon 14 skipping mechanism
- Both missense and truncating are valid disease mechanisms in MET
BP2 No evidence of this variant being observed in trans with a known pathogenic variant for a fully penetrant dominant disorder. MET-associated conditions are typically autosomal dominant. Details ▾Hide ▴
Evidence considered
- No in trans observation data available
- MET conditions are autosomal dominant
- not recessive
BP5 No alternate molecular cause for the observed phenotype has been identified in this case. BP5 requires the variant to be found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause identified in case materials
Still missing
- Patient phenotype data not available
- cannot assess whether alternate cause could exist
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
BP7 BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.226G>A, p.Glu76Lys) that results in an amino acid substitution. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- c.226G>A is a missense substitution
- not a synonymous variant
- Results in p.Glu76Lys amino acid change
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant c.226G>A (p.Glu76Lys) does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants under the ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 does not apply to missense substitutions. Details ▾Hide ▴
Evidence considered
- Variant class is missense substitution (p.E76K)
- not a predicted null variant
- pvs1_variant_assessment confirms variant_bucket='other'
- apply_generic_pvs1_framework=false
Sources
PM5 N/ANo same-residue pathogenic missense comparator variants were identified. The PM5 candidate pipeline returned 0 candidates and was unable to confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
- PM5 candidate pipeline: 0 candidates at residue E76
Sources
pm5_candidates
BP3 N/AThis is a substitution variant, not an in-frame indel in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework (Richards et al. 2015, PMID:25741868) and no CSPEC/VCEP-specific definition has been retrieved for MET. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MET
- Transcript
- NM_001127500.3
- Coding (HGVS c.)
- NM_001127500.3:c.226G>A
- Protein (HGVS p.)
- NP_001120972.1:p.(Glu76Lys)
- GRCh38
- chr7:116699310 G>A
- GRCh37
- chr7:116339364 G>A
- COSMIC
- COSV100577327
Gene diagram
Every interpreted variant in MET, mapped onto the exon structure of NM_001127500.3. Select a row to find it on the plot.
METNM_001127500.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MET
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,614,028 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,028 alleles · 0 hom
| European (non-Finnish)1 / 1,179,956 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19568e-07; MAF= 0.00006%, 1/1614028 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47489e-07; MAF= 0.00008%, 1/1179956 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.097
- BayesDel
- -0.574
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict a benign impact: REVEL score 0.097 (benign, well below ~0.5 threshold), BayesDel score -0.574 (benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). Consistent benign prediction across independent in silico tools supports BP4 at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.097 (benign)
- BayesDel: -0.574 (benign)
- SpliceAI: max delta 0.00
- no splicing effect predicted
- HCI Prior: not available for MET
Sources
PP3 Multiple lines of in silico evidence predict a benign effect: REVEL score 0.097 (benign, well below the ~0.5 pathogenic threshold), BayesDel score -0.574 (benign-leaning), and SpliceAI max delta 0.00 (no predicted splice impact). These scores do not support a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.097 (benign)
- BayesDel: -0.574 (benign)
- SpliceAI: max delta 0.00 (no splice effect)
Sources
BP7 BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.226G>A, p.Glu76Lys) that results in an amino acid substitution. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- c.226G>A is a missense substitution
- not a synonymous variant
- Results in p.Glu76Lys amino acid change
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.097. BayesDel score = -0.573908.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,028 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001127500.3%3Ac.226G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-116339364-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-116699310-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-116699310-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127500.3%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/MET/E76K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=130233854
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19568e-07; MAF= 0.00006%, 1/1614028 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47489e-07; MAF= 0.00008%, 1/1179956 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.097. BayesDel score = -0.573908.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MET, a receptor tyrosine kinase, is recurrently altered by mutation or amplification in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100577327, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.