Classification rationale

BP4 VUS

MET c.1063G>A missense · exon 2

BP4 (Supporting): SpliceAI predicts no splice impact (max delta score 0.001, well below the no-impact threshold). Final classification: VUS, reached under the generic ACMG/AMP 2015 framework because a single supporting benign criterion is insufficient to classify the variant.

BP4 → VUS

Gene diagram · NM_001127500.3 · variants mapped to exon structure

MET NM_001127500.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 23 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

BP4 supporting Benign

Met (Supporting): SpliceAI max delta score 0.001 predicts no splice impact, supporting no splicing effect.

SpliceAI raw scores: DS_AG=0.0, DS_AL=0.0, DS_DG=0.001, DS_DL=0.0, max_delta_score=0.001; evidence_sentence 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).' (prefetch.json/evidence.json spliceai block). SpliceAI delta scores this far below 0.1 are interpreted as no predicted splicing effect per the original SpliceAI validation study (Jaganathan et al., Cell 2019, PMID 30661751), supporting BP4 at supporting strength.

spliceai ↗

Assessed · not applied · 5 not met · 18 not assessed

Pathogenic

PS1 Not assessed: no pathogenic comparator producing the identical amino acid change (p.Glu355Lys) via a different nucleotide change was identified.

PS2 Not assessed: no confirmed de novo occurrence with validated maternity and paternity is documented.

PS3 Not assessed: no validated functional assay data for p.Glu355Lys (e.g., kinase activation, transformation) were available.

PS4 Not assessed: no variant-specific case-control comparison or enrichment statistic was available.

PM1 Not assessed: p.Glu355Lys lies in the HGF-binding semaphorin domain, but that domain tolerates benign variation and cancerhotspots.org reports no hotspot at E355.

PM2 Not met: variant is present in population databases — gnomAD v4.1 reports 60 alleles, so it is not absent from controls.

PM3 Not assessed: no data show this variant in trans with a pathogenic variant for a recessive condition.

PM5 Not assessed: no alternate pathogenic missense change at codon 355 (e.g., p.Glu355Asp) was identified as a comparator.

PM6 Not assessed: no suspected de novo occurrence without confirmed parental relationships is documented.

PP1 Not assessed: no family segregation observations (affected relatives, informative meioses) are documented.

PP2 Not assessed: MET's disease mechanisms are mixed (activating kinase-domain missense vs.

PP3 Not met: SpliceAI predicts no splice impact (max delta 0.001), and REVEL 0.31 falls below the PP3-supporting threshold of ≥0.644.

PP4 Not assessed: no patient phenotype or disease-specific clinical findings were provided for this variant.

PP5 Not assessed: no ClinVar expert-panel Pathogenic or Likely pathogenic classification exists for this exact variant.

Benign

BA1 Not met: gnomAD v4.1 allele frequency is 0.00376% (60/1,596,674 alleles), far below the benign stand-alone threshold.

BS1 Not met: highest population allele frequency (0.00943%) is far below the 0.3% benign threshold.

BS2 Not assessed: no phenotype-confirmed healthy adults carrying the variant are documented, and no homozygotes were observed.

BS3 Not assessed: no validated functional assay showing normal activity for this variant was available.

BS4 Not assessed: no unaffected relatives known to carry the variant are documented.

BP1 Not met: MET disease is primarily caused by activating missense variants, not truncating variants, so BP1's premise does not apply.

BP2 Not assessed: no co-occurrence data show this variant with a pathogenic variant in the same individual.

BP5 Not assessed: no confirmed alternative molecular diagnosis in a patient carrying this variant was provided.

BP6 Not assessed: no ClinVar expert-panel Benign or Likely benign classification exists for this exact variant.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.75781e-05; MAF= 0.00376%, 60/1596674 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 9.42863e-05; MAF= 0.00943%, 7/74242 alleles, homozygotes = 0); grpmax FAF= 4.409e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.98571e-05; MAF= 0.00299%, 7/234450 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000131199; MAF= 0.01312%, 2/15244 alleles, homozygotes = 0); grpmax FAF= 2.266e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0038% · 60 / 1,596,674
0 hom · FAF 0.0044%

African/African American 7 / 74,242	0.0094%
European (non-Finnish) 47 / 1,172,068	0.004%
Ashkenazi Jewish 1 / 28,556	0.0035%
Remaining individuals 2 / 61,674	0.0032%
East Asian 1 / 44,724	0.0022%
European (Finnish) 1 / 63,358	0.0016%
South Asian 1 / 87,514	0.0011%

+ 3 not observed (Admixed American, Amish, Middle Eastern)

gnomAD v2.1

0.003% · 7 / 234,450
0 hom · FAF 0.0023%

African/African American 2 / 15,244	0.013%
European (Finnish) 1 / 20,596	0.0049%
South Asian 1 / 26,234	0.0038%
European (non-Finnish) 3 / 108,392	0.0028%

+ 4 not observed (Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 219769)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.31. BayesDel score = -0.169214.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59257220, n = 4 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

19723643 ↗ Ethnic differences and functional analysis of MET mutations in lung cancer. CLINVAR

20139696 ↗ MET molecular mechanisms and therapies in lung cancer. CLINVAR

21904579 ↗ The role of the c-Met pathway in lung cancer and the potential for targeted therapy. CLINVAR

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. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

24319509 ↗ Canadian guideline on genetic screening for hereditary renal cell cancers. CLINVAR

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. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR