NM_001127500.3:c.226G>A

MET · NP_001120972.1:p.(Glu76Lys) · NM_001127500.3

GRCh37: chr7:116339364 G>A · GRCh38: chr7:116699310 G>A

Gene: MET Transcript: NM_001127500.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MET

Transcript

NM_001127500.3

Protein

NP_001120972.1:p.(Glu76Lys)

gnomAD AF

6.195679381026847e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense 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.	pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not met	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.
PS3	Not met	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.	oncokb revel bayesdel
PS4	Not met	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.	gnomad_v4 clinvar
PS5	N/A	PS5 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.
PM1	Not met	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not met	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.
PP1	Not met	No co-segregation data is available for this variant. No family studies have been performed or reported.
PP2	Not met	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.	revel bayesdel
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	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.
PP5	Not met	This variant is absent from ClinVar. No reputable source (clinical diagnostic laboratory, expert panel) has classified this variant as pathogenic.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not met	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.	gnomad_v4
BS3	Not met	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.	revel bayesdel
BS4	Not met	No segregation data is available. BS4 requires lack of segregation in affected family members.
BP1	Not met	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.
BP2	Not met	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.
BP3	N/A	This is a substitution variant, not an in-frame indel in a repetitive region.
BP4	Met	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 bayesdel spliceai
BP5	Not met	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.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	Not met	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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.