Variant classification summary

NM_000245.4:c.3682G>A

MET · NP_000236.2:p.(Asp1228Asn) · NM_000245.4

GRCh37: chr7:116423407 G>A · GRCh38: chr7:116783353 G>A

Gene: MET Transcript: NM_000245.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

MET

Transcript

NM_000245.4

Protein

NP_000236.2:p.(Asp1228Asn)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting because the variant is absent from the queried gnomAD datasets.

2

VUS: PP3 supporting because REVEL is 0.723, above the applied supporting threshold.

3

VUS: two supporting criteria satisfy no generic ACMG pathogenic, likely pathogenic, benign, or likely benign rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, PM2 supporting plus PP3 supporting does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination, so the call is VUS.

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 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: D1228N was reported in acquired drug resistance, but no previously established pathogenic same-amino-acid variant was identified.	PMID:28522754 clinvar
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history status, or confirmed maternity and paternity is available for this variant.
PS3	Not assessed	Not assessed: no validated, controlled functional assay directly testing MET p.Asp1228Asn is available; the reported experiments tested other MET substitutions.	PMID:28522754 PMID:27694386
PS4	Not assessed	Not assessed: no case-control counts, case frequency, odds ratio, relative risk, or confidence interval are available to test OR/RR >5.0 with a CI excluding 1.0.	PMID:27694386 PMID:28522754 gnomad_v2 gnomad_v4
PM1	Not assessed	Not assessed: D1228 is in the ATP docking pocket and a reported hotspot, but absence of benign variation across the relevant region is unestablished.	PMID:28522754 hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed allele frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no parent/offspring testing or documented trans relationship with a pathogenic variant is available.	PMID:27694386 PMID:28522754
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: D1228V is a same-residue resistance mutation, but it was not determined pathogenic under ACMG/AMP disease-classification evidence.	PMID:27694386
PM6	Not assessed	Not assessed: no proband-level assumed de novo observation or parental testing information is documented for this variant.
PP1	Not assessed	Not assessed: no affected relatives, informative genotypes, or co-segregating meioses are documented for this variant.
PP2	Not assessed	Not assessed: validated gene-level evidence for both low benign missense variation and a common missense disease mechanism is unavailable.
PP3	Met	Met at supporting strength: REVEL 0.723 exceeds the generic PP3 threshold of 0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not documented, so specificity for a single-gene disease cannot be evaluated.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant; the Pathogenic OMIM record has no assertion criteria and the laboratory record is uncertain significance.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF approaching the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no grpmax FAF reaches the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy-adult, homozygous, heterozygous, or hemizygous observation is available for this variant.
BS3	Not assessed	Not assessed: no controlled functional or splicing study directly shows that MET p.Asp1228Asn has no damaging effect.	PMID:28522754 PMID:27694386
BS4	Not assessed	Not assessed: no tested affected relatives or documented discordant genotype–phenotype observations are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the evidence does not establish that MET disease is primarily caused by truncating variants.
BP2	Not assessed	Not assessed: no documented cis/trans relationship with a pathogenic variant is available for this variant.	PMID:27694386 PMID:28522754
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.723 is above the generic BP4 supporting cutoff of 0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no documented patient case links this exact variant to a disease with an established alternate molecular basis.	PMID:27694386 PMID:28522754
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification; available submissions are Pathogenic without criteria or uncertain significance.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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