LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-08
Case ID: NM_005228.4_c.2573T_G_20260908_012038
Framework: ACMG/AMP 2015
Variant classification summary

NM_005228.4:c.2573T>G

EGFR  · NP_005219.2:p.(Leu858Arg)  · NM_005228.4
GRCh37: chr7:55259515 T>G  ·  GRCh38: chr7:55191822 T>G
Gene: EGFR Transcript: NM_005228.4
Final call
Likely Pathogenic
PS3 strong PM2 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
EGFR
Transcript
NM_005228.4
Protein
NP_005219.2:p.(Leu858Arg)
gnomAD AF
ClinVar
drug response
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 strong: three independent assays show L858R drives sustained ~2-3x EGF-induced EGFR autophosphorylation and ~10-50x gefitinib/erlotinib hypersensitivity versus wild-type.
2
PM2 moderate: the variant is absent (0 alleles) from gnomAD v2.1, v4.1, non-cancer subsets, and gnomAD-Canada, below the <0.1% rarity threshold.
Final determination: Under the generic ACMG/AMP 2015 combination rules, one strong pathogenic criterion (PS3) plus one moderate pathogenic criterion (PM2) maps to Likely Pathogenic.
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 PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005228.4:c.2573T>G in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Leu858Arg). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: no alternate-nucleotide change producing p.Leu858Arg with an established pathogenic classification was identified in ClinVar variation 16609 or the reviewed literature.
generic_acmg_combination_rules clinvar pm5_candidates PMID:15118073 PMID:15118125 PMID:15329413
PS2 Not assessed Not assessed: no proband or parental germline results exist, and published L858R cases are somatic tumor mutations with wild-type matched normal tissue, not de novo events.
clinvar PMID:15118073 PMID:15118125 PMID:15329413
PS3 Met Met: three independent validated assays show L858R gives sustained ~2-3x EGF-induced EGFR autophosphorylation and ~10-50x gefitinib hypersensitivity versus wild-type.
PMID:15118073 PMID:15118125 PMID:15329413 PMID:34526717
PS4 Not assessed Not assessed: no germline case-control study of this exact variant exists; all enrichment data (e.g., 8/9 TKI responders vs 0/7 non-responders, P<0.001) are somatic tumor or drug-response series, not PS4 case-control prevalence.
PMID:15118073 PMID:15118125 PMID:15329413 PMID:15897572 gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM1 Not met Not met: no VCEP-approved critical domain table exists for EGFR, and residue 858's hotspot/domain evidence is somatic (TK activation loop, DFG-adjacent), not an established germline functional domain.
generic_acmg_combination_rules PMID:15329413 PMID:15118125 PMID:15118073 gnomad_v2 gnomad_v4
PM2 Met Met at moderate strength: 0 alleles across gnomAD v2.1, v4.1, non-cancer subsets, and gnomAD-Canada, below the <0.1% PM2 threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3 N/A Not applicable: PM3 requires a phase-known second pathogenic variant in a recessive disorder, but all observations are heterozygous somatic gain-of-function tumor mutations with wild-type normal tissue.
generic_acmg_combination_rules clinvar PMID:15118073 PMID:15118125 PMID:15329413
PM4 N/A PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_005228.4:c.2573T>G in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Leu858Arg). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no different missense change at EGFR residue 858 with an established pathogenic classification was identified in ClinVar or the reviewed full-text literature.
generic_acmg_combination_rules clinvar pm5_candidates PMID:15118073 PMID:15118125 PMID:15329413
PM6 Not assessed Not assessed: no assumed de novo germline observation exists, and reviewed literature documents L858R as somatic (wild-type normal tissue), not a germline event.
clinvar PMID:15118073 PMID:15118125 PMID:15329413
PP1 Not assessed Not assessed: no affected-family segregation data exist in any source; fetched full texts lack pedigree content, and reported L858R is somatic in tumors.
clinvar PMID:15118073 PMID:15118125 PMID:15329413
PP2 Not assessed Not assessed: no gene-level data demonstrate a low benign missense rate for EGFR, and no authoritative evidence establishes missense as a common germline disease mechanism.
generic_acmg_combination_rules pvs1_gene_context pvs1_variant_assessment
PP3 Not assessed Not assessed: this missense variant has no calibrated REVEL/BayesDel score available to test PP3, and SpliceAI (max delta 0.013) is not the applicable path for a deep exonic change.
PP4 Not assessed Not assessed: no proband phenotype or family history is recorded for this case, so phenotype specificity for EGFR (PP4) cannot be evaluated.
generic_acmg_combination_rules
PP5 Not met Not met: the only ClinVar expert-panel assertion for this exact variant (ClinPGx, SCV000268169) is 'drug response' (gefitinib efficacy), not Pathogenic/Likely pathogenic, so PP5's required expert-panel classification is absent.
clinvar
BA1 Not met Not met: gnomAD v2.1, v4.1, and non-cancer subsets report 0 alleles, far below the >1% BA1 stand-alone threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1 Not met Not met: 0 alleles observed in gnomAD v2.1, v4.1, and non-cancer subsets, below the >0.3% BS1 frequency threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2 Not met Not met: no healthy adult carriers or homozygotes documented; the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3 Not met Not met: well-established assays show a damaging activating effect (~2-3x sustained autophosphorylation, ~10-50x TKI sensitivity), the opposite of the required no-effect.
PMID:15118073 PMID:15118125 PMID:15329413 spliceai
BS4 Not assessed Not assessed: no affected or unaffected relative genotypes exist to show non-segregation, and population absence in gnomAD is not BS4 evidence.
clinvar gnomad_v2 gnomad_v4 gnomad_canada PMID:15118073 PMID:15118125 PMID:15329413
BP1 Not assessed Not assessed: no authoritative evidence establishes that EGFR germline disease is primarily caused by truncating variants, so BP1's gene-mechanism prerequisite cannot be confirmed.
generic_acmg_combination_rules pvs1_gene_context pvs1_variant_assessment
BP2 Not met Not met: no proband shows EGFR c.2573T>G in trans with a pathogenic variant in dominant disease or in cis with one - all observations are monoallelic, heterozygous, and somatic.
generic_acmg_combination_rules clinvar PMID:15118073 PMID:15118125 PMID:15329413
BP3 N/A BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005228.4:c.2573T>G in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Leu858Arg). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not assessed Not assessed: no calibrated REVEL/BayesDel score is available to test BP4 for this missense variant; SpliceAI max delta 0.013 is out of scope for this deep exonic change.
BP5 Not assessed Not assessed: the case has no proband-level data (no phenotype, no alternative-variant or alternate-cause testing), so an alternate molecular basis of disease (BP5) cannot be evaluated.
generic_acmg_combination_rules
BP6 Not met Not met: no ClinVar expert-panel Benign/Likely benign assertion exists for this variant; the only panel assertion (ClinPGx SCV000268169) is 'drug response', and no benign submission of any kind is present.
clinvar
BP7 N/A BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005228.4:c.2573T>G in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Leu858Arg). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
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.