Variant classification summary

NM_005228.5:c.2156G>C

EGFR · NP_005219.2:p.(Gly719Ala) · NM_005228.5

GRCh37: chr7:55241708 G>C · GRCh38: chr7:55174015 G>C

Gene: EGFR Transcript: NM_005228.5

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting PP3 moderate

Variant details

Gene

EGFR

Transcript

NM_005228.5

Protein

NP_005219.2:p.(Gly719Ala)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong, with G719A causing transformation and ligand-independent EGFR activation in variant-specific assays.

2

Likely Pathogenic: PM1 moderate, because EGFR G719 is a statistically significant hotspot in the receptor tyrosine-kinase domain.

3

Likely Pathogenic: PM2 supporting, because the variant is absent from gnomAD v2.1 and v4.1.

4

Likely Pathogenic: PP3 moderate, because REVEL 0.824 exceeds the calibrated moderate threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one Strong pathogenic criterion plus one or two Moderate pathogenic criteria supports Likely Pathogenic; PM2 and PP3 provide additional supporting evidence.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no different-nucleotide EGFR variant producing the same pathogenic p.Gly719Ala change was documented.
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history assessment, or confirmed maternity and paternity testing establishes a de novo occurrence.
PS3	Met	Met, strong: G719A drove IL-3-independent growth and focus formation, while EGFR pTyr1068 phosphorylation was 0.89 versus 0.21 for wild type.	PMID:26206867 PMID:27294619
PS4	Not assessed	Not assessed: one G719A tumor among 59 affected patients was reported, but no control count or OR with a confidence interval was provided.	PMID:15738541 PMID:31825714 PMID:31931137 gnomad_v2 gnomad_v4
PM1	Met	Met: EGFR G719 is a reported statistically significant hotspot, and p.Gly719Ala lies in the receptor tyrosine-kinase domain.	hotspots PMID:27294619 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive inheritance, pathogenic second allele, or parental/offspring testing establishes this variant in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no independently pathogenic alternative missense substitution at EGFR residue 719 was documented.	pm5_candidates
PM6	Not assessed	Not assessed: no documented disease proband or assumed de novo result is available, with no parental-testing information to distinguish PM6 from PS2.
PP1	Not assessed	Not assessed: zero affected relatives and zero informative meioses are documented for evaluating co-segregation of the variant with disease.
PP2	Not assessed	Not assessed: functional EGFR missense evidence is available, but no gene-level benign-missense-rate assessment was provided.	PMID:27294619
PP3	Met	Met at moderate strength: missense REVEL score 0.824 meets the PP3 moderate threshold of >= 0.773.	revel
PP4	Not assessed	Not assessed: no patient-specific phenotype or family history is available, and NSCLC is not specific to a single genetic etiology.	clinvar
PP5	Not met	Not met: ClinVar shows exact-variant pathogenic laboratory submissions but 0 expert-panel submissions, so the required PP5 source is absent.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency reaches the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: no gnomAD allele frequency or grpmax FAF is available because the variant is absent, versus the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier or homozygote observation is documented, and a fully penetrant early-onset disorder model is not established.
BS3	Not met	Not met: variant-specific assays showed oncogenic transformation and ligand-independent EGFR activation rather than preserved protein function or normal splicing.	PMID:26206867 PMID:27294619
BS4	Not assessed	Not assessed: no tested affected relatives or family-level phenotype and genotype data are available to demonstrate lack of segregation.
BP1	Not met	Not met: EGFR evidence documents activating missense disease biology rather than a primarily truncating disease mechanism.	PMID:27294619 PMID:26206867
BP2	Not assessed	Not assessed: no pathogenic variant is documented in trans for a fully penetrant dominant disorder or in cis in any inheritance pattern.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.824 exceeds the BP4 supporting cutoff of <= 0.29.	revel
BP5	Not assessed	Not assessed: no specific case documents an alternate molecular basis alongside EGFR c.2156G>C/p.Gly719Ala.	PMID:15738541 PMID:31825714 PMID:31931137
BP6	Not met	Not met: no exact-variant benign expert-panel classification exists; ClinVar reports pathogenic laboratory submissions and 0 expert-panel submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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