Variant classification summary

NM_005228.5:c.2573T>G

EGFR · NP_005219.2:p.(Leu858Arg) · NM_005228.5

GRCh37: chr7:55259515 T>G · GRCh38: chr7:55191822 T>G

Gene: EGFR Transcript: NM_005228.5

Final call

Pathogenic

PS3 strong PM1 moderate PM2 supporting PP3 strong BP4 supporting

Variant details

Gene

EGFR

Transcript

NM_005228.5

Protein

NP_005219.2:p.(Leu858Arg)

gnomAD AF

ClinVar

drug response

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: independent functional studies show altered EGFR signaling and substantially increased TKI sensitivity for L858R.

2

Pathogenic: L858R lies in the EGFR tyrosine-kinase domain and a statistically significant cancer hotspot.

3

Pathogenic: the variant is absent from gnomAD v2.1 and v4.1, supporting extreme rarity.

4

Pathogenic: REVEL 0.961 exceeds the calibrated PP3 strong threshold of 0.932.

5

Applied benign evidence: SpliceAI max delta 0.013 supports BP4, but does not override two strong pathogenic criteria.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PP3) support a Pathogenic classification, with PM1 and PM2 providing additional pathogenic evidence despite supporting BP4.

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_005228.5: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: published reports confirm EGFR p.Leu858Arg but do not establish an independent nucleotide change producing the same amino-acid substitution.	PMID:15329413 PMID:15118125 PMID:15897572
PS2	Not assessed	Not assessed: no documented proband variant with confirmed absence in both parents or verified maternity, paternity, and de novo observations.
PS3	Met	Met at strong: EGFR L858R showed altered phosphorylation and approximately 10-fold greater TKI sensitivity than wild type in one study, with independent signaling inhibition in another.	PMID:15329413 PMID:15118125 generic_acmg_combination_rules
PS4	Not assessed	Not assessed: the exact variant appears in lung-cancer cohorts, but no case-control enrichment statistic or validated prevalence comparison is reported.	PMID:15329413 PMID:15118125 PMID:15897572
PM1	Met	Met, moderate: EGFR L858R is residue 858 in the tyrosine kinase domain and lies in a statistically significant hotspot.	oncokb PMID:15897572 PMID:34526717
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with an allele frequency <=0.0001 for PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation documents EGFR p.Leu858Arg with a pathogenic variant in trans or establishes recessive inheritance.
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_005228.5: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 validated pathogenic or likely pathogenic alternate missense change at EGFR residue 858 is documented.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no proband phenotype and no suspected de novo occurrence without parental testing are documented for this variant.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or phenotype-concordant co-segregation data are provided.
PP2	Not assessed	Not assessed: EGFR missense predominance and rarity of benign missense variation are not established by the available gene-level evidence.
PP3	Met	Met, strong: REVEL 0.961 exceeds the calibrated PP3 strong threshold of 0.932 for missense variants.	revel spliceai
PP4	Not met	Not met: the available phenotype is broad NSCLC and drug response, not a highly specific phenotype for a defined Mendelian disorder.	clinvar PMID:15329413 PMID:15897572
PP5	Not met	Not met: the exact-variant ClinVar expert-panel classification is drug response, while Pathogenic and Likely pathogenic labels are non-expert submissions.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having the >=0.05 allele frequency required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no variant observations, so the allele frequency does not reach the >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: the variant is absent from the available gnomAD datasets, with no healthy-adult or homozygote observations supporting BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign-function assay was identified, while available experiments show altered EGFR signaling and increased inhibitor sensitivity.	PMID:15329413 PMID:15118125
BS4	Not assessed	Not assessed: no reliably phenotyped affected individual or family series demonstrates absence of the variant despite an informative segregation opportunity.
BP1	Not assessed	Not assessed: a predominantly truncating EGFR disease mechanism has not been established for this interpretation.
BP2	Not assessed	Not assessed: no affected-proband observation documents this variant in trans with a pathogenic variant or in cis with a benign variant.
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_005228.5: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	Met	Met, supporting: SpliceAI max delta 0.013 is below the calibrated BP4 supporting threshold of 0.1 for predicted splice neutrality.	spliceai revel
BP5	Not assessed	Not assessed: no pathogenic variant in an alternative gene is reported to explain the phenotype instead of EGFR L858R.	clinvar
BP6	Not met	Not met: no exact-variant ClinVar expert-panel classification of Benign or Likely benign is present; the expert-panel label is drug response.	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_005228.5: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

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