Classification rationale

PM2 BP4 VUS

MET c.226G>A

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.¹ 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.² 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.³ 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).⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗oncokb ↗

4 generic_acmg_combination_rules

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

MET NM_001127500.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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.

Absent from gnomAD v2.1Absent from gnomAD-Canada v1.0gnomAD v4.1: 1/1

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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.

REVEL: 0.097 (benign)BayesDel: -0.574 (benign)SpliceAI: max delta 0.00

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No different nucleotide change at codon 76 resulting in the same amino acid substitution (Glu76Lys) has been identified and classified as pathogenic.

PS2 No de novo occurrence data is available for NM_001127500.3:c.226G>A.

PS3 No functional data exists for NM_001127500.3:c.226G>A (p.E76K).

PS4 No case-control, cohort, or case series data demonstrate enrichment of this variant in affected individuals compared to controls.

PM1 Position Glu76 is in the SEMA domain of MET, but this residue is not a statistically significant mutational hotspot per CancerHotspots.org.

PM6 No de novo data is available for this variant.

PP1 No co-segregation data is available for this variant.

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.

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).

PP4 No specific patient phenotype or family history data is available for assessment.

PP5 This variant is absent from ClinVar.

Benign

BA1 The variant allele frequency in gnomAD v4.1 (AF = 6.2e-7, ~0.00006%) is far below the >1% threshold for BA1.

BS1 The variant allele frequency (AF = 6.2e-7, ~0.00006%) is well below the >0.3% BS1 threshold for a rare variant.

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).

BS3 No well-established functional studies demonstrate a neutral effect for this variant.

BS4 No segregation data is 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).

BP2 No evidence of this variant being observed in trans with a known pathogenic variant for a fully penetrant dominant disorder.

BP5 No alternate molecular cause for the observed phenotype has been identified in this case.

BP6 This variant is absent from ClinVar.

BP7 BP7 applies to synonymous (silent) variants with no predicted splice impact.

N/A · 3 PVS1 · PM5 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

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).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,614,028
0 hom

European (non-Finnish)

1 / 1,179,956

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

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.

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; COSV100577327, n = 1 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