About MET
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MET c.3852+5T>C, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). Multiple computational lines of evidence suggest no impact on splicing.
BP6Supporting
BP6 · supporting
This variant is classified as Likely benign by multiple clinical laboratories in ClinVar (5 laboratories: GeneDx, Ambry Genetics, Labcorp/Invitae, Myriad Genetics, PreventionGenetics). The aggregate ClinVar classification is Likely benign with criteria provided by single submitters.
Recorded classification: Likely benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting, BP6 supporting; combination = 2 supporting benign, which maps to Likely Benign.
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
353 / 1,614,074 alleles
gnomAD v4.1: 353 / 1,614,074 alleles. Recorded AF 0.000218701. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.91126e-05; MAF= 0.00891%, 25/280544 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000420168; MAF= 0.04202%, 3/7140 alleles, homozygotes = 0); grpmax FAF= 0.00012413.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005428292259255238, 10/18422 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.090 maximum delta
Recorded SpliceAI maximum delta score: 0.090. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
7 reported laboratory submissions
5 Likely benign · 2 Uncertain significance.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV104627101, n = 1 times).
Context only
COSMIC ↗
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 · 18 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001127500.3:c.3852+5T>C is an intronic substitution at the +5 position of the splice donor in intron 19 of MET. PVS1 is not applicable as the variant falls outside the canonical ±1,2 splice consensus and no functional data demonstrate a null effect.
SpliceAI predicts no significant splice impact (max delta score 0.09), meeting BP4 at the supporting level.
The variant is present in gnomAD v2.1 at an allele frequency of 0.0089% (25/280,544 alleles) and in gnomAD v4.1 at 0.022% (353/1,614,074 alleles) including 1 homozygote, which is inconsistent with a rare pathogenic variant for a dominant cancer predisposition disorder but does not meet BS1 (>0.3%) or BA1 (>1%) thresholds.
ClinVar reports a consensus classification of Likely benign from 5 clinical testing laboratories (GeneDx, Ambry Genetics, Labcorp/Invitae, Myriad Genetics, PreventionGenetics), meeting BP6 at the supporting level. Two laboratories report Uncertain significance.
No functional studies, segregation data, de novo observations, case-control studies, or variant-specific literature were identified for this variant; all remaining pathogenic and benign criteria are either not met or not applicable.
No criteria match.
Met · 2
BP4 SupportingSpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). Multiple computational lines of evidence suggest no impact on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.09 — predicts no significant donor loss
- acceptor gain
- or other splice alteration
Sources
BP6 SupportingThis variant is classified as Likely benign by multiple clinical laboratories in ClinVar (5 laboratories: GeneDx, Ambry Genetics, Labcorp/Invitae, Myriad Genetics, PreventionGenetics). The aggregate ClinVar classification is Likely benign with criteria provided by single submitters. Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign by 5 clinical testing laboratories
- 2 laboratories report Uncertain significance
- No laboratory reports pathogenic or likely pathogenic
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo observations with both maternity and paternity confirmed have been identified for this variant in ClinVar or published literature. Details ▾Hide ▴
Evidence considered
- No de novo reports found in ClinVar submissions or literature
Still missing
- No trio sequencing or de novo confirmation studies available
Sources
PS3 No well-established in vitro or in vivo functional studies have been performed for this specific variant. SpliceAI predicts no significant splice impact (max delta 0.09), but computational prediction alone does not satisfy PS3 requirements for functional evidence of a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.09 predicts no significant splice impact
- No minigene
- RT-PCR
- or protein functional assays available
Still missing
- No variant-specific functional splicing or protein assays performed
Sources
PS4 No published case-control studies demonstrate statistically significant enrichment of this variant in affected individuals versus controls. The variant is present in gnomAD at low frequency but without disease association data. Details ▾Hide ▴
Evidence considered
- Absent from case-control studies
- gnomAD v2.1 AF 0.0089% (25/280
- 544 alleles)
- gnomAD v4.1 AF 0.022% (353/1
- 614
- 074 alleles)
Still missing
- No controlled disease-association studies including this variant
Sources
PM1 Located in intron 19 of MET; there is no evidence that this splice donor region is a recognized mutational hotspot or a critical functional domain without benign variation in MET. Details ▾Hide ▴
Evidence considered
- No mutational hotspot identified at intron 19 splice donor of MET
- No known pathogenic variant cluster at this site
Still missing
- No hotspot annotation for MET intron 19 donor region
PM2 Present in gnomAD v4.1 at 0.022% (353/1,614,074 alleles) with 1 homozygote and in v2.1 at 0.0089% (25/280,544 alleles). The allele count and homozygote observation in v4.1 are inconsistent with an ultra-rare pathogenic variant in a dominantly inherited cancer predisposition gene, even though the overall frequency is below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 25/280
- 544 alleles (AF 0.0089%)
- 0 homozygotes
- gnomAD v4.1: 353/1
- 614
- 074 alleles (AF 0.022%)
- 1 homozygote
- gnomAD-Canada: absent
Sources
PM6 No de novo observations without confirmation of maternity and paternity have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature
Still missing
- No de novo observation data available
Sources
PP1 No co-segregation data in multiple affected family members has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family segregation studies available
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta 0.09). REVEL and BayesDel scores are not available for this intronic variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.09 — no significant splicing impact predicted
- REVEL not available
- BayesDel not available
Sources
PP4 No patient phenotype or family history data were provided for this case; cannot evaluate whether the phenotype is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No proband phenotype or clinical history available for assessment
Still missing
- No clinical phenotype data provided
PP5 No reputable source has recently reported this variant as pathogenic. ClinVar aggregate classification is Likely benign (5 clinical laboratories) with 2 laboratories reporting Uncertain significance. The cited ClinVar PMIDs (25741868, 28492532) are methodology guideline papers that do not mention this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign (5 labs)
- Uncertain significance (2 labs)
- No PMIDs provide variant-specific pathogenic assertion
Sources
BA1 Highest population allele frequency is 0.022% (gnomAD v4.1), well below the >1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF 0.022% (353/1
- 614
- 074)
- gnomAD v2.1 overall AF 0.0089% (25/280
- 544)
- Both well below BA1 threshold of >1%
Sources
BS1 Highest population allele frequency is 0.022% (gnomAD v4.1) and highest subpopulation AF is 0.042% (gnomAD v2.1 OTH), both below the >0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF 0.022%
- gnomAD v2.1 max subpopulation AF 0.042% (OTH)
- Both below BS1 threshold of >0.3%
Sources
BS2 No confirmed observation of this variant in healthy adult individuals for a fully penetrant early-onset disorder has been reported. The gnomAD homozygote observation (v4.1, n=1) lacks phenotypic confirmation. Details ▾Hide ▴
Evidence considered
- 1 homozygote in gnomAD v4.1 without phenotypic data
- No reported observation in confirmed healthy controls
Still missing
- No phenotypically confirmed healthy adult observations
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this specific variant. SpliceAI prediction (max delta 0.09) is computational only and does not constitute experimental functional evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.09 — computational prediction only
- No experimental splicing or protein functional assays performed
Still missing
- No experimental functional data demonstrating normal splicing or protein function
Sources
BS4 No segregation data in affected family members demonstrating lack of co-segregation with disease has been reported. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No segregation studies available for BS4 evaluation
BP2 No observation of this variant in cis with a pathogenic MET variant has been reported. Details ▾Hide ▴
Evidence considered
- No co-occurrence data with pathogenic MET variants available
Still missing
- No cis/trans phase data available
BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴
Evidence considered
- No cases with alternate molecular diagnosis reported
Still missing
- No data on co-occurrence with an alternate molecular cause
PS5 This variant has not been classified as pathogenic by a reputable source. ClinVar consensus classification is Likely benign (5 clinical laboratories) with 2 laboratories reporting Uncertain significance. PS5 requires a reputable source to have recently reported the variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Likely benign (5 labs)
- Uncertain significance (2 labs)
- No expert panel or reputable source classifying as pathogenic
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AVariant is at the +5 position of the splice donor in intron 19, outside the canonical ±1,2 splice consensus. The PVS1 variant assessment classifies it as bucket 'other' with apply_generic_pvs1_framework=false; SpliceAI predicts no significant splicing impact (max delta 0.09), and no functional data demonstrate a null effect. PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is at +5 splice donor position
- not canonical ±1
- 2
- SpliceAI max delta 0.09 indicates no significant splice impact
- PVS1 variant assessment explicitly classifies as not eligible for generic PVS1 framework
Sources
PS1 N/AIntronic variant with no amino acid change; PS1 requires the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Evidence considered
- Intronic variant without amino acid consequence
PM5 N/AIntronic variant with no amino acid residue; classic same-residue PM5 semantics cannot be applied. PM5 candidates confirms ineligible. Details ▾Hide ▴
Evidence considered
- Intronic variant — no protein residue for PM5 comparator search
Sources
pm5_candidates
PP2 N/AIntronic variant; PP2 applies only to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not missense
BP1 N/AIntronic variant; BP1 applies only to missense variants in genes where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not missense
BP3 N/AVariant is a substitution; BP3 applies only to in-frame deletions or insertions in repetitive regions. Details ▾Hide ▴
Evidence considered
- Substitution variant
- not an in-frame indel
BP7 N/AIntronic variant located at +5 of the splice donor; BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not synonymous
Identifiers
- Gene
- MET
- Transcript
- NM_001127500.3
- Coding (HGVS c.)
- NM_001127500.3:c.3852+5T>C
- Protein (HGVS p.)
- NP_001120972.1:p.?
- GRCh38
- chr7:116783474 T>C
- GRCh37
- chr7:116423528 T>C
- ClinVar
- 184563
- COSMIC
- COSV104627101
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
353 / 1,614,074 alleles
AF 0.000219 · 1 homozygotes · FAF 0.000257
gnomAD v2.1
25 / 280,544 alleles
AF 8.91e-05 · 0 homozygotes · FAF 0.000124
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00022 · 353 / 1,614,074 alleles · 1 hom · FAF 0.00026
| European (non-Finnish)333 / 1,179,970 | 0.00028 |
| Remaining individuals10 / 62,506 | 0.000161 hom |
| African/African American6 / 75,048 | 8e-05 |
| Admixed American2 / 60,022 | 3.3e-05 |
| European (Finnish)1 / 64,038 | 1.6e-05 |
| South Asian1 / 91,086 | 1.1e-05 |
0 alternate alleles recorded in 4 other groups: Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 8.9e-05 · 25 / 280,544 alleles · 0 hom · FAF 0.00012
| Remaining individuals3 / 7,140 | 0.00042 |
| European (non-Finnish)22 / 128,432 | 0.00017 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000218701; MAF= 0.02187%, 353/1614074 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000282211; MAF= 0.02822%, 333/1179970 alleles, homozygotes = 0); grpmax FAF= 0.00025697.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.91126e-05; MAF= 0.00891%, 25/280544 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000420168; MAF= 0.04202%, 3/7140 alleles, homozygotes = 0); grpmax FAF= 0.00012413.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005428292259255238, 10/18422 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). Multiple computational lines of evidence suggest no impact on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.09 — predicts no significant donor loss
- acceptor gain
- or other splice alteration
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta 0.09). REVEL and BayesDel scores are not available for this intronic variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.09 — no significant splicing impact predicted
- REVEL not available
- BayesDel not available
Sources
BP7 N/AIntronic variant located at +5 of the splice donor; BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015Standards and guidelines for the interpretation of sequence variants (ACMG/AMP 2015 consensus). This is a methodology paper that establishes the variant classification framework; it does not discuss NM_001127500.3:c.3852+5T>C or any specific MET variant.Does not name this variant
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PMID 24319509 ↗Canadian guideline on genetic screening for hereditary renal cell cancers.Reaume MN et al. · 2013Canadian guideline on genetic screening for hereditary renal cell cancers. Discusses referral criteria and genes including MET, VHL, FH at the gene level for hereditary RCC syndromes. NM_001127500.3:c.3852+5T>C is not mentioned.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. General clinical guidance document; does not discuss specific MET variants.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Methodology paper describing an evidence-based variant classification system. Does not mention NM_001127500.3:c.3852+5T>C.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
353 / 1,614,074 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.090
Open source ↗
ClinVar
5 Likely benign · 2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/184563/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-116423528-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-116783474-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-116783474-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127500.3%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/MET/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=130223911
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= 0.000218701; MAF= 0.02187%, 353/1614074 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000282211; MAF= 0.02822%, 333/1179970 alleles, homozygotes = 0); grpmax FAF= 0.00025697.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.91126e-05; MAF= 0.00891%, 25/280544 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000420168; MAF= 0.04202%, 3/7140 alleles, homozygotes = 0); grpmax FAF= 0.00012413.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005428292259255238, 10/18422 alleles, homozygotes = 0).
ClinVar
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV104627101, n = 1 times).