LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-30
Case ID: NM_005228.5_c.2155G_A_20261030_131521
Framework: ACMG/AMP 2015
Variant classification summary

NM_005228.5:c.2155G>A

EGFR  · NP_005219.2:p.(Gly719Ser)  · NM_005228.5
GRCh37: chr7:55241707 G>A  ·  GRCh38: chr7:55174014 G>A
Gene: EGFR Transcript: NM_005228.5
Final call
Likely Pathogenic
PS3 strong PM2 supporting PP3 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
EGFR
Transcript
NM_005228.5
Protein
NP_005219.2:p.(Gly719Ser)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PS3 strong supports damaging EGFR p.Gly719Ser function through transformation, constitutive signaling, and tumor formation.
2
Likely Pathogenic: PP3 moderate is supported by REVEL 0.853 exceeding the 0.773 threshold.
3
Likely Pathogenic: PM2 supporting is supported by absence from available gnomAD datasets.
Final determination: Under the generic ACMG/AMP 2015 fallback rules, one strong pathogenic criterion plus one moderate pathogenic criterion supports Likely Pathogenic; PM2 supporting is additional concordant 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 established pathogenic comparator with the same Gly719Ser amino-acid change but a different nucleotide change was documented.
PMID:16187797 PMID:16199108 PMID:23468066 clinvar
PS2 Not assessed Not assessed: no germline proband record, confirmed maternity and paternity, or documented absence of family history is available.
PMID:16187797 PMID:16199108 PMID:23468066
PS3 Met Met, strong: EGFR p.G719S produced transformation, constitutive signaling, drug-sensitive growth, and mouse tumors, including approximately 15-fold increased anchorage-independent growth.
PMID:16187797
PS4 Not assessed Not assessed: exact-variant case reports lack matched control counts, so the required OR >5.0 and 95% CI excluding 1.0 cannot be calculated.
PMID:16187797 PMID:16199108 PMID:23468066 PMID:18573086
PM1 Not assessed Not assessed: Gly719 is in the kinase domain and a reported hotspot, but absence of benign variation for that region was not established.
PMID:18573086 hotspots
PM2 Met Met at supporting strength: the variant is absent across available gnomAD datasets, giving observed frequency 0, below the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4 gnomad_canada
PM3 Not assessed Not assessed: tumor reports show EGFR c.2155G>A with p.E709A, but no pathogenic second allele or parental testing establishes trans phase.
PMID:23468066 PMID:16199108
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 different missense substitution at Gly719 with an established pathogenic determination was documented.
pm5_candidates clinvar PMID:16187797 PMID:16199108 PMID:23468066
PM6 Not assessed Not assessed: no germline proband record or parental testing, even without confirmation, is documented for this variant.
PMID:16187797 PMID:16199108 PMID:23468066
PP1 Not assessed Not assessed: zero affected relatives, informative meioses, or phenotype-consistent genotype segregation observations are documented.
PMID:16187797 PMID:16199108 PMID:23468066
PP2 Not assessed Not assessed: EGFR missense disease-mechanism evidence is available, but no validated gene-level low benign-missense rate was provided.
PMID:16187797 oncokb PMID:18573086
PP3 Met Met at moderate strength: REVEL 0.853 meets the generic PP3 moderate threshold of >=0.773 for this missense variant.
revel
PP4 Not assessed Not assessed: the available records describe somatic NSCLC tumor findings, not a patient phenotype or family history specific to a single-gene disease.
PMID:16199108 PMID:23468066
PP5 Not met Not met: ClinVar has zero expert-panel submissions, and its exact-variant Likely pathogenic assertion is a non-expert submission without criteria.
clinvar oncokb
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than present at the >=0.05 BA1 frequency threshold.
gnomad_v2 gnomad_v4
BS1 Not met Not met: all available gnomAD datasets report absence, so no grpmax FAF reaches the generic BS1 threshold of 0.01.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not assessed Not assessed: no healthy adult germline observation is documented, and the required early-onset full-penetrance disease context is not established.
gnomad_v2 gnomad_v4 gnomad_canada
BS3 Not met Not met: EGFR p.G719S showed EGF-independent transformation, constitutive signaling, increased growth, and tumor formation rather than absence of damaging effect.
PMID:16187797
BS4 Not assessed Not assessed: no affected family members with documented genotypes are available for a non-segregation comparison.
PMID:16187797 PMID:16199108 PMID:23468066
BP1 Not assessed Not assessed: no disease-specific evidence showed that EGFR-related disease is caused primarily by truncating rather than missense variants.
PMID:16187797 PMID:18573086 oncokb
BP2 Not assessed Not assessed: a tumor co-occurrence with p.E709A lacks phase determination and does not establish the second variant as pathogenic.
PMID:23468066 PMID:16199108
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: REVEL 0.853 is above the generic BP4 supporting threshold of <=0.29 for this missense variant.
revel
BP5 Not assessed Not assessed: one tumor had a second EGFR variant, but no report establishes an alternate molecular basis as the cause of disease.
PMID:23468066
BP6 Not met Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.
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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