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

Likely Pathogenic

PS3 strong PM1 moderate PM2 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

PS3 (Strong): functional assays show T790M sustains kinase signaling and markedly reduces gefitinib/erlotinib sensitivity.

PM1 (Moderate): Thr790 is the EGFR kinase gatekeeper residue in the catalytic cleft, a statistically significant mutational hotspot.

PM2 (Supporting): extremely rare in gnomAD v4.1 (0.0000099) with zero homozygotes.

Overall: Likely Pathogenic, from PS3 strong plus PM1 moderate under the generic ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015: one Strong pathogenic criterion plus one Moderate pathogenic criterion supports 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 is a missense change, p.(Thr790Met), so the null-variant premise PVS1 requires does not hold.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no record establishes this exact amino-acid change as a pathogenic germline variant for an applicable EGFR disease.	PMID:15728811 PMID:15737014 clinvar
PS2	Not assessed	Not assessed: no de novo occurrence and no parental testing are documented for this variant.
PS3	Met	Met at strong strength: engineered cell and biochemical assays show T790M sustains kinase signaling and markedly reduces gefitinib/erlotinib sensitivity.	PMID:15728811 PMID:15737014 PMID:18227510 PMID:34526717
PS4	Not assessed	Not assessed: no germline case-control comparison or odds ratio shows enrichment in affected individuals versus controls.	PMID:15737014 PMID:29151359
PM1	Met	Met at moderate: Thr790 is the EGFR kinase gatekeeper residue in the catalytic cleft and a statistically significant mutational hotspot.	PMID:15728811 PMID:18227510
PM2	Met	Met at supporting: gnomAD v4.1 frequency 0.0000099 (16/1,614,100 alleles) with zero homozygotes, below the 0.1% rarity threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected individual carrying a second established pathogenic EGFR variant in trans is documented.	PMID:15737014 PMID:15728811
PM4	N/A	Not applicable: this missense change does not alter protein length, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate pathogenic amino-acid substitution at EGFR residue 790 was identified for comparison.	pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence without parental testing is documented for this variant.
PP1	Not assessed	Not assessed: no pedigree or genotype data from informative relatives were available to evaluate segregation.
PP2	Not assessed	Not assessed: no applicable germline EGFR disease is established in which missense variants are a common pathogenic mechanism.
PP3	Not met	Not met: REVEL 0.529 falls inside the 0.250-0.750 gray zone, below the threshold supporting a pathogenic computational call.	revel
PP4	Not assessed	Not assessed: no individual-level phenotype or pedigree was supplied to judge specificity for a germline EGFR disorder.
PP5	Not met	Not met: the exact-variant ClinVar expert-panel submissions are drug-response classifications, not Pathogenic or Likely Pathogenic.	clinvar
BA1	Not met	Not met: the highest population frequency is 0.016% in gnomAD v2.1, far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest population frequency is 0.016% in gnomAD v2.1, well below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD reports zero homozygotes, and no unaffected homozygous carriers are documented.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional study shows normal activity, and available assays instead report altered kinase activity and inhibitor resistance.
BS4	Not assessed	Not assessed: no genotyped relatives were available to test whether the variant fails to segregate with disease.
BP1	Not assessed	Not assessed: no applicable germline EGFR disease is established as predominantly caused by truncating rather than missense variants.
BP2	Not assessed	Not assessed: no germline observation of this variant in trans or in cis with a pathogenic variant is documented.	PMID:15737014
BP3	N/A	Not applicable: this missense change creates no in-frame length change in a repeat region, which BP3 requires.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.529 sits in the 0.250-0.750 gray zone, so no computational benign support applies.	revel
BP5	Not assessed	Not assessed: no alternative molecular diagnosis explaining the individual's phenotype was identified.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification exists, only drug-response entries.	clinvar
BP7	N/A	Not applicable: the variant is missense and alters the protein sequence, so the silent-variant premise BP7 requires does not hold.	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.