Variant classification summary

NM_001127500.3:c.1063G>A

MET · NP_001120972.1:p.(Glu355Lys) · NM_001127500.3

GRCh37: chr7:116340201 G>A · GRCh38: chr7:116700147 G>A

Gene: MET Transcript: NM_001127500.3

Final call

VUS

BP4 supporting

Variant details

Gene

MET

Transcript

NM_001127500.3

Protein

NP_001120972.1:p.(Glu355Lys)

gnomAD AF

3.757811550761145e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): SpliceAI predicts no splice impact (max delta score 0.001, well below the no-impact threshold).

2

Final classification: VUS, reached under the generic ACMG/AMP 2015 framework because a single supporting benign criterion is insufficient to classify the variant.

Final determination:

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	Not applicable: PVS1 applies only to null variants (nonsense, frameshift, canonical splice-site, start-loss, stop-loss), and this is a missense substitution (p.Glu355Lys) that does not trigger such a mechanism.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no pathogenic comparator producing the identical amino acid change (p.Glu355Lys) via a different nucleotide change was identified.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with validated maternity and paternity is documented.
PS3	Not assessed	Not assessed: no validated functional assay data for p.Glu355Lys (e.g., kinase activation, transformation) were available.
PS4	Not assessed	Not assessed: no variant-specific case-control comparison or enrichment statistic was available.
PM1	Not assessed	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.	PMID:19723643 gnomad_v2 gnomad_v4
PM2	Not met	Not met: variant is present in population databases — gnomAD v4.1 reports 60 alleles, so it is not absent from controls.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no data show this variant in trans with a pathogenic variant for a recessive condition.
PM4	N/A	Not applicable: PM4 applies to protein-length changes (in-frame indels, stop-loss); this missense substitution does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate pathogenic missense change at codon 355 (e.g., p.Glu355Asp) was identified as a comparator.	pm5_candidates
PM6	Not assessed	Not assessed: no suspected de novo occurrence without confirmed parental relationships is documented.
PP1	Not assessed	Not assessed: no family segregation observations (affected relatives, informative meioses) are documented.
PP2	Not assessed	Not assessed: MET's disease mechanisms are mixed (activating kinase-domain missense vs. recessive loss-of-function), so a low rate of benign missense variation is not established.	PMID:19723643 clinvar
PP3	Not met	Not met: SpliceAI predicts no splice impact (max delta 0.001), and REVEL 0.31 falls below the PP3-supporting threshold of ≥0.644.	spliceai revel
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific clinical findings were provided for this variant.
PP5	Not assessed	Not assessed: no ClinVar expert-panel Pathogenic or Likely pathogenic classification exists for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 0.00376% (60/1,596,674 alleles), far below the benign stand-alone threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: highest population allele frequency (0.00943%) is far below the 0.3% benign threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no phenotype-confirmed healthy adults carrying the variant are documented, and no homozygotes were observed.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no validated functional assay showing normal activity for this variant was available.
BS4	Not assessed	Not assessed: no unaffected relatives known to carry the variant are documented.
BP1	Not met	Not met: MET disease is primarily caused by activating missense variants, not truncating variants, so BP1's premise does not apply.	PMID:19723643
BP2	Not assessed	Not assessed: no co-occurrence data show this variant with a pathogenic variant in the same individual.
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions; this missense substitution does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI max delta score 0.001 predicts no splice impact, supporting no splicing effect.	spliceai
BP5	Not assessed	Not assessed: no confirmed alternative molecular diagnosis in a patient carrying this variant was provided.
BP6	Not assessed	Not assessed: no ClinVar expert-panel Benign or Likely benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this missense substitution alters the encoded amino acid (p.Glu355Lys).	generic_acmg_combination_rules

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