LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-10
Case ID: NM_005228.4_c.2155G_A_v9_20260909
Framework: ACMG/AMP 2015
Variant classification summary

NM_005228.4:c.2155G>A

EGFR  · NP_005219.2:p.(Gly719Ser)  · NM_005228.4
GRCh37: chr7:55241707 G>A  ·  GRCh38: chr7:55174014 G>A
Gene: EGFR Transcript: NM_005228.4
Final call
Likely Pathogenic
PS3 strong PM1 moderate PM2 supporting PP3 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
EGFR
Transcript
NM_005228.4
Protein
NP_005219.2:p.(Gly719Ser)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 strong: exact-variant assays demonstrated activating transformation, abnormal signaling, inhibitor-sensitive growth, and in vivo tumor activity.
2
PM1 moderate: p.Gly719Ser lies in the EGFR kinase ATP-binding loop at hotspot residue G719.
3
PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.
4
PP3 moderate: REVEL 0.853 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 a Likely Pathogenic classification; PS3 strong, PM1 moderate, and PP3 moderate meet this rule.
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_005228.4:c.2155G>A in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Gly719Ser). 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 assessed Not assessed: p.Gly719Ser is reported, but no reviewed source establishes an independently known pathogenic same-amino-acid comparator for PS1.
PMID:16187797 PMID:21531810 PMID:29141884 generic_acmg_combination_rules
PS2 Not assessed Not assessed: no documented proband-level de novo result with parental testing, confirmed maternity and paternity, and phenotype-consistent clinical evidence.
PS3 Met Met, strong: EGFR p.G719S produced ligand-independent transformation and IL-3-independent Ba/F3 growth in independent cellular assays, with in vivo tumor formation and inhibitor-sensitive signaling.
PMID:16187797 PMID:16204070 PMID:29141884
PS4 Not assessed Not assessed: exact EGFR G719S reports lack matched-control prevalence, odds ratio, p-value, or a validated PS4 enrichment threshold.
PMID:21531810 PMID:16199108 PMID:23468066
PM1 Met Met at moderate: p.Gly719Ser lies in the EGFR kinase ATP-binding loop, a critical functional region, and residue G719 is a documented statistical hotspot.
PMID:16204070 generic_acmg_combination_rules
PM2 Met Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3 Not assessed Not assessed: no germline affected-proband observation or documented cis/trans phase is available for EGFR p.Gly719Ser.
PMID:21531810 PMID:23468066
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_005228.4:c.2155G>A in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Gly719Ser). 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: G719C and G719A are mentioned, but neither is established as a known pathogenic comparator required for PM5.
PMID:29141884 pm5_candidates generic_acmg_combination_rules
PM6 Not assessed Not assessed: no clinical unconfirmed de novo occurrence is reported; available G719S evidence is somatic tumor or experimental evidence.
PP1 Not assessed Not assessed: zero informative affected-relative meioses or familial genotype–phenotype observations are documented for segregation analysis.
PP2 Not assessed Not assessed: variant-specific EGFR oncogenic evidence is available, but no validated gene-level missense-versus-benign-variation analysis supports PP2.
generic_acmg_combination_rules
PP3 Met Met at moderate strength: REVEL 0.853 exceeds the >=0.773 calibrated moderate PP3 threshold.
revel
PP4 Not assessed Not assessed: EGFR G719S is reported in NSCLC, but no individual phenotype-specificity assessment or validated PP4 threshold is provided.
PMID:21531810 PMID:16199108 PMID:23468066
PP5 Not met Not met: the exact ClinVar record has 0 expert-panel submissions, and its Likely pathogenic assertion is non-expert without assertion criteria.
clinvar
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, below the generic BA1 allele-frequency threshold of >=0.05.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, below the generic BS1 allele-frequency threshold of >=0.01.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2 Not met Not met: gnomAD reports no variant observations, so no healthy-individual or homozygote observation supports BS2.
gnomad_v2 gnomad_v4
BS3 Not met Not met: EGFR p.G719S showed activating transformation and IL-3-independent growth rather than normal function in multiple exact-variant assays.
PMID:16187797 PMID:16204070 PMID:29141884
BS4 Not assessed Not assessed: no informative unaffected relatives with documented genotype and phenotype are available to demonstrate non-segregation.
BP1 Not met Not met: EGFR evidence supports an activating missense mechanism, including G719S transformation, rather than a truncation-dominant disease mechanism.
PMID:16187797 PMID:16204070 generic_acmg_combination_rules
BP2 Not assessed Not assessed: co-occurring EGFR variants are reported in tumors, but their benign/pathogenic status and cis/trans phase are undocumented.
PMID:21531810 PMID:23468066
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_005228.4:c.2155G>A in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Gly719Ser). 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 Not met Not met: REVEL 0.853 is above the <=0.29 maximum calibrated supporting BP4 threshold.
revel
BP5 Not assessed Not assessed: no affected individual with a documented alternative molecular cause is provided for BP5 evaluation.
BP6 Not met Not met: ClinVar reports 0 expert-panel submissions and no exact-variant Benign or Likely benign expert-panel classification.
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_005228.4:c.2155G>A in EGFR is a missense substitution predicted to produce NP_005219.2:p.(Gly719Ser). 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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