LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-12
Case ID: NM_001127500.2_c.737C_T_20260812_130341
Framework: ACMG/AMP 2015
Variant classification summary

NM_001127500.2:c.737C>T

MET  · NP_001120972.1:p.(Pro246Leu)  · NM_001127500.2
GRCh37: chr7:116339875 C>T  ·  GRCh38: chr7:116699821 C>T
Gene: MET Transcript: NM_001127500.2
Final call
VUS
PM2 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MET
Transcript
NM_001127500.2
Protein
NP_001120972.1:p.(Pro246Leu)
gnomAD AF
1.239095955590801e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): variant essentially absent from population databases — gnomAD v4.1 AF 1.24e-06 (2/1,614,080 alleles, 0 homozygotes); absent from gnomAD v2.1 and gnomAD-Canada v1.0.
2
BP4 (Supporting): REVEL 0.287 falls within the ClinGen SVI-calibrated BP4-supporting interval (0.183-0.290), predicting a benign/tolerated effect; SpliceAI max delta 0.00 corroborates no splice impact.
3
Final classification VUS: the single supporting pathogenic-leaning criterion (PM2) and single supporting benign-leaning criterion (BP4) satisfy no generic ACMG/AMP combination rule, so the result defaults to VUS.
Final determination: Generic ACMG/AMP 2015 fallback combination rule: with applied criteria PM2 (supporting) and BP4 (supporting) only, no pathogenic (e.g., PVS1 + 1 PS, 2 PS, 1 PS + 3 PM), likely pathogenic (e.g., 3 PM, 1 PM + 4 PP, 1 PS + 1 PM), benign (BA1 alone or 2 BS), or likely benign (1 BS + 1 BP or 2 BP) combination is satisfied; all remaining combinations, including 1 supporting + 1 supporting in opposite directions, default to 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 Not applicable: this missense substitution does not belong to the null-variant classes (nonsense, frameshift, splice-consensus, initiation-loss, stop-loss) PVS1 requires.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: no pathogenic submission for p.(Pro246Leu) exists in ClinVar; the only entry is a single-submitter Uncertain significance record.
clinvar pm5_candidates
PS2 Not assessed Not assessed: no de novo occurrence with confirmed maternity and paternity has been reported for this variant.
clinvar PMID:25394175 generic_acmg_combination_rules
PS3 Not assessed Not assessed: no well-established functional studies of this variant exist; in silico scores (REVEL 0.287, SpliceAI 0.00) cannot satisfy PS3.
oncokb clinvar PMID:25394175
PS4 Not assessed Not assessed: no case-control or cohort enrichment data exist for this variant; the sole ClinVar entry supplies no affected-case counts.
clinvar gnomad_v4 PMID:25394175 generic_acmg_combination_rules
PM1 Not met Not met: residue 246 is not a statistically significant cancer hotspot (Cancer Hotspots no_result), and no critical functional domain around it could be established.
oncokb pvs1_variant_assessment
PM2 Met Met (supporting): essentially absent from population databases — gnomAD v4.1 AF 1.24e-06 (2/1,614,080 alleles, 0 homozygotes); absent from gnomAD v2.1 and gnomAD-Canada v1.0.
gnomad_v4 gnomad_v2 gnomad_canada
PM3 N/A Not applicable: MET germline disease is autosomal dominant, so the recessive-disorder trans requirement (pathogenic variant in trans) is unmet.
generic_acmg_combination_rules clinvar gnomad_v4 pvs1_gene_context
PM4 N/A Not applicable: this missense substitution does not change protein length, so the in-frame indel/stop-loss criterion has nothing to evaluate.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: no pathogenic missense variant at a different amino acid at residue 246 is documented (absence-of-evidence determination).
pm5_candidates clinvar
PM6 Not assessed Not assessed: no de novo report — confirmed or unconfirmed — for this variant exists.
clinvar PMID:25394175 generic_acmg_combination_rules
PP1 Not assessed Not assessed: no family segregation data exist — no affected relatives tested and no meioses observed.
clinvar PMID:25394175 generic_acmg_combination_rules
PP2 Not assessed Not assessed: no gene-level missense constraint metric (e.g., gnomAD missense z-score) is available to evaluate the low-benign-missense-rate prong.
oncokb generic_acmg_combination_rules
PP3 Not met Not met: REVEL 0.287 is far below the >=0.644 PP3-supporting threshold, and SpliceAI max delta 0.00 predicts no splice impact.
revel spliceai bayesdel generic_acmg_combination_rules
PP4 Not assessed Not assessed: no proband phenotype, family history, or clinical summary is available to assess specificity for MET-associated disease.
clinvar generic_acmg_combination_rules
PP5 Not met Not met: no ClinVar expert-panel Pathogenic/Likely pathogenic classification exists for this exact variant; only a single-laboratory Uncertain significance entry.
clinvar PMID:25394175 generic_acmg_combination_rules
BA1 Not met Not met: gnomAD v4.1 AF 1.24e-06 is more than four orders of magnitude below the >5% BA1 threshold.
gnomad_v4 gnomad_v2 gnomad_canada
BS1 Not met Not met: observed frequency (1.24e-06) is orders of magnitude below any plausible expected-frequency threshold for a germline cancer-predisposition disorder.
gnomad_v4 gnomad_v2 gnomad_canada
BS2 Not met Not met: only 2 unconfirmed heterozygous carriers and 0 homozygotes in gnomAD v4.1; no phenotype-verified unaffected controls.
gnomad_v4 gnomad_v2 gnomad_canada
BS3 Not assessed Not assessed: no well-established functional studies showing no damaging effect are available; in silico predictions alone cannot satisfy BS3.
oncokb clinvar PMID:25394175
BS4 Not assessed Not assessed: no family segregation or non-segregation data exist for this variant.
clinvar PMID:25394175 generic_acmg_combination_rules
BP1 Not met Not met: MET disease is not predominantly truncating — germline activating missense variants are an established mechanism (hereditary papillary renal cell carcinoma).
oncokb pvs1_gene_context generic_acmg_combination_rules
BP2 Not assessed Not assessed: no phase, co-occurrence, or parental-testing data exist to evaluate trans/cis observations with a pathogenic variant.
generic_acmg_combination_rules clinvar gnomad_v4
BP3 N/A Not applicable: this missense substitution does not alter protein length within a repeat region, so the criterion has nothing to evaluate.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met (supporting): REVEL 0.287 falls within the ClinGen SVI-calibrated BP4-supporting interval (0.183-0.290); SpliceAI max delta 0.00 corroborates no splice impact.
revel spliceai bayesdel generic_acmg_combination_rules
BP5 Not assessed Not assessed: no proband-level molecular workup or alternative genetic diagnosis is available to evaluate an alternative disease cause.
generic_acmg_combination_rules
BP6 Not met Not met: no ClinVar expert-panel Benign/Likely benign classification exists for this exact variant.
clinvar generic_acmg_combination_rules
BP7 N/A Not applicable: this is a missense substitution, not a synonymous variant, so the silent-variant criterion does not apply.
generic_acmg_combination_rules
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