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

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting PP3 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

PS3 (Strong): variant-specific cell assays showed increased, prolonged EGF-induced activation and increased gefitinib/erlotinib sensitivity versus wild-type EGFR.

2

PM1 (Moderate): L858R is a recurrent activating hotspot at residue 858 within the EGFR tyrosine kinase domain.

3

PM2 (Supporting): the exact c.2573T>G (p.Leu858Arg) variant is absent from gnomAD v2.1 and v4.1.

4

PP3 (Supporting): REVEL 0.961 exceeds the 0.750 missense threshold.

5

Overall: Likely Pathogenic, from 1 strong plus 1 moderate criterion.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one moderate pathogenic criterion yields a Likely Pathogenic classification.

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 (p.Leu858Arg) is not a null variant, so nonsense-mediated decay or truncation does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the publications report c.2573T>G itself, not a different nucleotide change producing the same p.Leu858Arg substitution.	PMID:15118073 PMID:15118125 PMID:15329413 PMID:15897572
PS2	Not assessed	Not assessed: no proband germline result with confirmed parental testing was available, and the literature describes somatic lung tumors.
PS3	Met	Met (strong): variant-specific cell assays showed increased, prolonged EGF-induced activation and markedly increased gefitinib/erlotinib sensitivity versus wild-type EGFR.	PMID:15118073 PMID:15329413
PS4	Not assessed	Not assessed: no case-control comparison, control frequency, or odds ratio for a defined germline EGFR condition was available.	generic_acmg_combination_rules PMID:15897572
PM1	Met	Met (moderate): L858R is a recurrent activating hotspot at residue 858 within the EGFR tyrosine kinase domain, an established critical functional domain.	PMID:15118073 PMID:15329413 oncokb
PM2	Met	Met (supporting): the exact c.2573T>G (p.Leu858Arg) variant is absent from gnomAD v2.1 and v4.1.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: reports describe L858R as a somatic tumor mutation, with no second pathogenic allele, trans phase, or recessive inheritance context.	PMID:15118073 PMID:15118125
PM4	N/A	Not applicable: this missense substitution causes no change in protein length, so the in-frame indel and stop-loss premise does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate missense substitution at EGFR residue 858 with an established pathogenic classification was identified.	PMID:15118073 PMID:15118125 PMID:15329413 PMID:15897572 pm5_candidates
PM6	Not assessed	Not assessed: no de novo germline observation with unconfirmed parentage was documented; the available evidence concerns somatic lung tumors.
PP1	Not assessed	Not assessed: no pedigree, family testing, or phenotype-segregation data were provided; the available publications are tumor cohorts.
PP2	Not assessed	Not assessed: no validated gene-level analysis showing that benign missense variation is uncommon for this EGFR clinical context was available.
PP3	Met	Met (supporting): REVEL 0.961 exceeds the PP3 missense threshold of >0.750.	revel
PP4	Not assessed	Not assessed: available sources describe somatic NSCLC and treatment response, not a phenotype specific for a germline EGFR disorder.	generic_acmg_combination_rules clinvar
PP5	Not met	Not met: the expert-panel ClinVar entry for this exact variant is drug response, not a Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no population allele frequency exceeds the stand-alone benign threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the exact variant is absent from gnomAD v2.1 and v4.1, so no frequency exceeds the disease-specific benign threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no observation in healthy adults, homozygote findings, or disease-specific penetrance data were available.
BS3	Not met	Not met: functional studies report increased EGF-induced activation and increased inhibitor sensitivity versus wild-type EGFR, not normal function.	PMID:15118073 PMID:15329413
BS4	Not assessed	Not assessed: no affected or unaffected relatives tested for the variant were documented, so non-segregation evidence cannot be evaluated.
BP1	Not assessed	Not assessed: truncating variants are not established as the predominant EGFR disease mechanism, so missense rarity cannot be inferred.
BP2	Not assessed	Not assessed: evidence is limited to somatic tumor reports, with no documented pathogenic allele in cis or trans.	PMID:15118073 PMID:15118125
BP3	N/A	Not applicable: this missense substitution is not an in-frame insertion or deletion within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.961 does not fall below the benign-supporting BP4 threshold of <0.250.	revel
BP5	Not assessed	Not assessed: no proband phenotype or independent alternate molecular diagnosis was supplied, so this criterion cannot be evaluated.
BP6	Not met	Not met: no expert-panel Benign or Likely benign classification exists for this variant; the expert-panel entry is drug response.	clinvar
BP7	N/A	Not applicable: the variant is missense rather than synonymous, so BP7's silent-variant splicing premise does not hold.	generic_acmg_combination_rules

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