Final classification

Likely Pathogenic

PS3PM1PM2PP3

EGFR

c.2155G>A

p.Gly719Ser

missense · exon 18

Gene context NCBI Gene ↗ OncoKB ↗

The EGFR gene encodes the epidermal growth factor receptor, a cell-surface protein that binds growth factors of the EGF family and, upon activation, dimerizes and triggers signaling pathways that drive cell proliferation, migration, and differentiation. EGFR is an oncogene: normally expressed at low levels in adult tissues, it becomes hyperactivated through mutation or gene amplification in many cancer types, including lung, brain, colorectal, and head and neck cancers. In non-small cell lung cancer, such activation can make tumors responsive to EGFR tyrosine kinase inhibitor drugs, although resistance can develop during treatment. EGFR has also been implicated in the excessive inflammatory response (cytokine storm) associated with severe COVID-19.

This variant

EGFR is an oncogene whose hyperactivated signaling can drive cancer development and may confer sensitivity to EGFR tyrosine kinase inhibitors.

Transcript

NM_005228.4

HGVS · transcript:coding

NM_005228.4:c.2155G>A

GRCh38

chr7:55174014 G>A

GRCh37

chr7:55241707 G>A

Likely Pathogenic: PS3 strong plus PM1 and PP3 moderate criteria, with PM2 supporting, satisfy the generic ACMG/AMP fallback combination.

Classification rationale

PS3PM1PM2PP3 Likely Pathogenic

EGFR c.2155G>A missense · exon 18

PS3 strong: exact-variant assays demonstrated activating transformation, abnormal signaling, inhibitor-sensitive growth, and in vivo tumor activity. PM1 moderate: p.Gly719Ser lies in the EGFR kinase ATP-binding loop at hotspot residue G719. PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1. PP3 moderate: REVEL 0.853 exceeds the calibrated moderate threshold.

PS3 + PM1 + PM2 + PP3 → Likely Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_005228.4 · variants mapped to exon structure

EGFR NM_005228.4

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 20 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

PS3 strong Pathogenic

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 directly tested EGFR G719S in NIH-3T3 and hTBE cells: the mutant caused ligand-independent transformation, anchorage-independent growth, constitutive EGFR/STAT3/Akt signaling, and tumors in immunocompromised mice; erlotinib inhibited the phenotype.PMID:16204070 directly tested EGFR-G719S in Ba/F3 cells: the mutant conferred IL-3-independent growth and constitutive EGFR, STAT5, ERK1/2, ERK5, and AKT phosphorylation; gefitinib inhibited growth with an approximately 140 nmol/L IC50.PMID:29141884 independently evaluated EGFR G719S in a MANO Ba/F3 assay and reported dose-dependent death with multiple EGFR TKIs, with additional xenograft depletion after erlotinib.

PMID:16187797 ↗PMID:16204070 ↗PMID:29141884 ↗

PM1 moderate Pathogenic

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 describes EGFR-G719S as located in the ATP-binding loop (p-loop) and reports constitutive receptor autophosphorylation, downstream signaling, and ligand-independent transformation.The Cancer Hotspots result identifies EGFR G719 as a statistically significant hotspot; the structured extraction is partially parsed but the corresponding screenshot is available for audit.No EGFR-specific VCEP domain table was available; therefore no authoritative domain-table exclusion or alternative strength rule could be applied.

PMID:16204070 ↗

PM2 supporting Pathogenic

Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with the <=0.0001 PM2 threshold.

The variant is reported absent from gnomAD v2.1 (GRCh37) and gnomAD v4.1 (GRCh38).The available gnomAD evidence also reports absence from the gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer subsets.The generic PM2 threshold of <=0.0001 and supporting-only strength were used under the ClinGen SVI recommendation described in the supplied calibration block, based on Richards et al. 2015 (PMID:25741868), because no EGFR-specific VCEP rule was available.

gnomad_v2 ↗gnomad_v4 ↗

PP3 moderate Pathogenic

Met at moderate strength: REVEL 0.853 exceeds the >=0.773 calibrated moderate PP3 threshold.

The case evidence reports REVEL 0.853 for NM_005228.4:c.2155G>A (p.Gly719Ser).The supplied ClinGen SVI REVEL calibration assigns PP3 moderate at REVEL >=0.773 (Pejaver et al. 2022, PMID:36413997).The variant is classified as missense, making the missense computational path applicable; BayesDel has no generic ACMG strength calibration and SpliceAI is reserved here for splice-region or intronic variants.

Assessed · not applied · 8 not met · 12 not assessed

Pathogenic

PS1 Not assessed: p.Gly719Ser is reported, but no reviewed source establishes an independently known pathogenic same-amino-acid comparator for PS1.

PS2 Not assessed: no documented proband-level de novo result with parental testing, confirmed maternity and paternity, and phenotype-consistent clinical evidence.

PS4 Not assessed: exact EGFR G719S reports lack matched-control prevalence, odds ratio, p-value, or a validated PS4 enrichment threshold.

PM3 Not assessed: no germline affected-proband observation or documented cis/trans phase is available for EGFR p.Gly719Ser.

PM5 Not assessed: G719C and G719A are mentioned, but neither is established as a known pathogenic comparator required for PM5.

PM6 Not assessed: no clinical unconfirmed de novo occurrence is reported; available G719S evidence is somatic tumor or experimental evidence.

PP1 Not assessed: zero informative affected-relative meioses or familial genotype–phenotype observations are documented for segregation analysis.

PP2 Not assessed: variant-specific EGFR oncogenic evidence is available, but no validated gene-level missense-versus-benign-variation analysis supports PP2.

PP4 Not assessed: EGFR G719S is reported in NSCLC, but no individual phenotype-specificity assessment or validated PP4 threshold is provided.

PP5 Not met: the exact ClinVar record has 0 expert-panel submissions, and its Likely pathogenic assertion is non-expert without assertion criteria.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, below the generic BA1 allele-frequency threshold of >=0.05.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, below the generic BS1 allele-frequency threshold of >=0.01.

BS2 Not met: gnomAD reports no variant observations, so no healthy-individual or homozygote observation supports BS2.

BS3 Not met: EGFR p.G719S showed activating transformation and IL-3-independent growth rather than normal function in multiple exact-variant assays.

BS4 Not assessed: no informative unaffected relatives with documented genotype and phenotype are available to demonstrate non-segregation.

BP1 Not met: EGFR evidence supports an activating missense mechanism, including G719S transformation, rather than a truncation-dominant disease mechanism.

BP2 Not assessed: co-occurring EGFR variants are reported in tumors, but their benign/pathogenic status and cis/trans phase are undocumented.

BP4 Not met: REVEL 0.853 is above the <=0.29 maximum calibrated supporting BP4 threshold.

BP5 Not assessed: no affected individual with a documented alternative molecular cause is provided for BP5 evaluation.

BP6 Not met: ClinVar reports 0 expert-panel submissions and no exact-variant Benign or Likely benign expert-panel classification.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as drug response (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 16612)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.853. BayesDel score = 0.356918.

SpliceAI ↗

Functional Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Hotspot

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51767289, n = 76 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.

Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.

PMID 16187797 ↗ ONCOKB · functional

Searched

c.2155G>Ap.G719SG719S

Found

The paper explicitly studied EGFR G719S and found that it enabled anchorage-independent growth without exogenous EGF, caused focus and tumor formation, and produced constitutive EGFR-pathway signaling.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 strong

Exact-variant cellular transformation, signaling, pharmacologic inhibition, and in vivo tumor evidence support abnormal function.

The L858R and G719S mutants were able to transform NIH-3T3 cells to anchorage independence in the absence of exogenous EGF, as assayed by colony formation in soft agar (Figure 1A, top photographs).

Location Results, Expression of Mutant EGFR Induces Oncogenic Transformation; Figure 1A · Context Site-directed EGFR mutagenesis followed by expression in NIH-3T3 and hTBE cells, with soft-agar, signaling, inhibitor-sensitivity, and mouse-tumor assays. · full text

Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression.

PMID 16204070 ↗ CLINVAR · functional

Searched

c.2155G>Ap.G719SG719SATP-binding loop

Found

The paper studied EGFR-G719S in Ba/F3 cells and found ligand-independent IL-3-independent proliferation, constitutive receptor autophosphorylation and downstream signaling, and localization of G719S to the ATP-binding loop.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 strong

Exact-variant IL-3-independent growth, constitutive signaling, and inhibitor-response data demonstrate abnormal activating function.

→PM1 moderate

Places G719S in the critical EGFR kinase ATP-binding loop and demonstrates functional activity there.

Strikingly, gefitinib seemed to inhibit growth of cells expressing the two EGFR mutants to different extents. IC50 for AG1478 is about 8 nmol/L in Ba/F3 cells expressing EGFRL858R and about 17 nmol/L in EGFR-G719S cells, whereas IC50 for gefitinib is about 20 nmol/L in EGFR-L858R-expressing cells and about 140 nmol/L in EGFR-G719S cells. Thus, the EGFR-G719S mutant seems clearly less sensitive to gefitinib.

Location Results, "Differential growth inhibition of epidermal growth factor receptor mutant-expressing Ba/F3 cells by gefitinib," paragraph 2 · Context Murine IL-3-dependent Ba/F3 cells expressing full-length EGFR-G719S, assessed by growth, phosphorylation, drug-response, and cell-cycle assays. · full text

A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer.

PMID 29141884 ↗ ONCOKB · functional

Searched

c.2155G>Ap.G719SG719SG719CG719A

Found

The paper evaluated EGFR G719S in a high-throughput functional assay and discussed alternate G719C and G719A substitutions with differing TKI sensitivity; it did not establish ACMG pathogenic classifications for those alternates.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 strong

Independent exact-variant functional screen and xenograft result corroborate abnormal EGFR G719S activity.

EGFR TKIs ... resulted in the dose-dependent death of cells for five TKI-sensitive EGFR mutants (L858R, E746_A750 del, G719S, E861Q, and S768I) in the pool.

Location Results, Establishment of a high-throughput functional assay; Figure 3A and Discussion · Context MANO functional assay in Ba/F3 cells with multiple EGFR TKIs and supporting 3T3-cell xenograft experiments. · full text

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

21531810 ↗ Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. ONCOKB

31825714 ↗ Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09). ONCOKB

31931137 ↗ Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases. ONCOKB

16199108 ↗ Epidermal growth factor receptor gene mutation in non-small cell lung cancer using highly sensitive and fast TaqMan PCR assay. CLINVAR

23468066 ↗ Increased detection rates of EGFR and KRAS mutations in NSCLC specimens with low tumour cell content by 454 deep sequencing. CLINVAR

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