Variant classification summary

NM_005228.5:c.2369C>T

EGFR · NP_005219.2:p.(Thr790Met) · NM_005228.5

GRCh37: chr7:55249071 C>T · GRCh38: chr7:55181378 C>T

Gene: EGFR Transcript: NM_005228.5

Final call

VUS

PS3 strong PM1 moderate PM2 supporting BP4 supporting

Variant details

Gene

EGFR

Transcript

NM_005228.5

Protein

NP_005219.2:p.(Thr790Met)

gnomAD AF

9.912644817545382e-06 (v4.1)

ClinVar

drug response

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: T790M showed increased EGFR catalytic activity and inhibitor resistance in concordant functional studies.

2

PM1 moderate: p.Thr790Met is located in the EGFR kinase catalytic cleft.

3

PM2 supporting: gnomAD v4.1 allele frequency is 9.91264e-06 with zero homozygotes.

4

BP4 supporting: SpliceAI max delta 0.002 meets the adjudicated BP4 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, conflicting pathogenic and benign evidence—including PS3 strong, PM1 moderate, PM2 supporting, and BP4 supporting—results in 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	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.2369C>T in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Thr790Met). 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 met	Not met: no alternate nucleotide substitution producing the same p.Thr790Met change was identified, although the submitted variant itself is well documented.	PMID:15728811 PMID:15737014 clinvar
PS2	Not assessed	Not assessed: no confirmed germline proband and no parental testing or de novo result are documented.
PS3	Met	Met, strong: EGFR T790M showed approximately fivefold higher catalytic activity than wild type and persistent phosphorylation despite gefitinib up to 2 µM.	PMID:15728811 PMID:15737014 PMID:18227510 PMID:34526717
PS4	Not met	Not met: available reports describe acquired drug resistance, not statistically enriched germline disease cases versus controls for PS4.	PMID:15737014 PMID:15728811 generic_acmg_combination_rules
PM1	Met	Met at moderate strength: p.Thr790Met is in the EGFR kinase catalytic cleft, with demonstrated effects on ATP affinity and kinase activity.	PMID:15728811 PMID:18227510
PM2	Met	Met at supporting: gnomAD v4.1 AF 9.91264e-06 is below the <=0.0001 PM2 threshold, with 0 homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected proband with a second pathogenic allele in trans or validated recessive EGFR inheritance was documented.
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.2369C>T in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Thr790Met). 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 verified different pathogenic missense variant at EGFR residue 790 was available for comparison.	pm5_candidates PMID:15728811 PMID:15737014
PM6	Not assessed	Not assessed: no phenotype-consistent presumed de novo germline observation without parental testing is documented.
PP1	Not assessed	Not assessed: zero informative germline meioses or family genotype-phenotype observations are documented.
PP2	Not assessed	Not assessed: no validated EGFR germline missense-mechanism and benign-variation framework was available to support PP2.
PP3	Not met	Not met: SpliceAI max delta 0.002 and REVEL 0.529 are below their generic PP3 supporting thresholds of 0.2 and 0.644.	spliceai revel bayesdel
PP4	Not assessed	Not assessed: no individual clinical phenotype or disease-specific specificity rule is available to evaluate PP4.	PMID:15737014 PMID:15728811
PP5	Not met	Not met: the exact-variant ClinVar expert panel reports drug response, not Pathogenic or Likely pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v4.1 all-comers AF 9.91264e-06 is far below the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest observed ancestry AF, 5.33803e-05 in gnomAD v4.1, is below the >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 and v2.1 each report 0 homozygotes, so no healthy-homozygote evidence supports BS2.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: T790M increased EGFR catalytic activity approximately fivefold rather than demonstrating normal function in validated cellular and biochemical assays.	PMID:15728811 PMID:15737014 PMID:18227510 PMID:34526717
BS4	Not assessed	Not assessed: no informative unaffected carriers or family non-segregation observations are documented.
BP1	Not assessed	Not assessed: no validated EGFR germline framework shows that truncating variants predominate and missense disease variants are uncommon.
BP2	Not assessed	Not assessed: the only phase observation places T790M in cis with L858R in a somatic tumor, not a validated germline affected-proband context.	PMID:15737014
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.2369C>T in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Thr790Met). 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 at supporting: SpliceAI max delta 0.002 meets the generic BP4 threshold of <=0.1, while REVEL 0.529 does not.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: no affected-individual diagnostic context or alternate pathogenic molecular explanation is documented.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification 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_005228.5:c.2369C>T in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Thr790Met). 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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