Variant classification summary

NM_005228.4:c.2237_2255delinsT

EGFR · NP_005219.2:p.(Glu746_Ser752delinsVal) · NM_005228.4

GRCh37: chr7:55242467 AATTAAGAGAAGCAACATC>T · GRCh38: chr7:55174774 AATTAAGAGAAGCAACATC>T

Gene: EGFR Transcript: NM_005228.4

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 supporting PM4 moderate

Variant details

Gene

EGFR

Transcript

NM_005228.4

Protein

NP_005219.2:p.(Glu746_Ser752delinsVal)

gnomAD AF

ClinVar

drug response

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The variant NM_005228.4:c.2237_2255delinsT (p.E746_S752delinsV) is an in-frame deletion-insertion in exon 19 of the EGFR tyrosine kinase domain, removing amino acids 746-752 and inserting a valine residue, which eliminates the conserved LREA motif critical for kinase autoinhibition.

2

Functional evidence demonstrates this variant causes gain-of-function EGFR kinase activation: the exact variant (del E746-S752insV) was associated with clinical gefitinib response in a lung adenocarcinoma patient (PMID:15710947), and related exon 19 deletions were shown in vitro to alter EGFR phosphorylation and confer TKI sensitivity (PMID:15329413). OncoKB classifies the variant as Oncogenic with gain-of-function effect.

3

The variant is located in the EGFR tyrosine kinase domain, a well-characterized critical functional domain that is a recurrent hotspot for activating mutations in NSCLC. The deletion removes the conserved LREA motif at codons 747-750 within the ATP-binding pocket.

4

The variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant not tolerated in the general population.

5

This in-frame deletion of 7 amino acids with insertion of a valine in a non-repeat, critical functional domain constitutes a significant protein length alteration expected to disrupt domain architecture.

6

The variant has been repeatedly observed as a somatic driver in lung adenocarcinoma (COSMIC, n=87) and is recognized in the curated OncoKB database as oncogenic, underscoring its established functional significance in cancer biology.

7

Met criteria: PS3 (moderate), PM1 (moderate), PM4 (moderate), PM2 (supporting). Three moderate and one supporting criterion meet the generic ACMG/AMP 2015 threshold for Likely Pathogenic classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Variant is an in-frame deletion-insertion (c.2237_2255delinsT, p.E746_S752delinsV) within the EGFR tyrosine kinase domain, not a nonsense, frameshift, or canonical ±1,2 splice consensus variant. Does not qualify for default PVS1 null-variant buckets per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	Variant is an in-frame deletion-insertion, not a missense change. PS1 classically applies to novel missense variants at the same codon as an established pathogenic missense variant. Not applicable to indel variants.
PS2	Not assessed	No data available regarding de novo occurrence with confirmed maternity and paternity.
PS3	Met	The exact variant (p.E746_S752delinsV) has been directly observed and characterized in a clinical-functional context. In Han et al. 2005 (PMID:15710947), a patient harboring this specific EGFR exon 19 deletion demonstrated a partial response to gefitinib with prolonged time to progression (22+ months) and overall survival (22+ months), consistent with an activating EGFR kinase domain mutation. Additional in vitro functional characterization of related exon 19 deletions (del L747-S752) by Pao et al. 2004 (PMID:15329413) demonstrated altered EGFR phosphorylation and increased sensitivity to tyrosine kinase inhibitors, confirming gain-of-function for this class of deletion. OncoKB classifies the variant as Oncogenic with gain-of-function effect, and the variant is recurrently observed in somatic cancers (COSMIC, n=87).	PMID:15710947 PMID:15329413 oncokb
PS4	Not assessed	No germline case-control or cohort data available. The variant is well-documented in somatic lung cancer (COSMIC, n=87) but this does not satisfy PS4 requirements for germline variant interpretation.
PS5	N/A	Variant is an in-frame deletion-insertion, not a single-nucleotide substitution. PS5 requires a different nucleotide change at the same position producing a different amino acid change, which is not applicable to multi-nucleotide indels.
PM1	Met	The variant deletes amino acids 746-752 within the EGFR tyrosine kinase domain, a well-characterized critical functional domain. This region encompasses the ATP-binding pocket and is a recognized hotspot for activating oncogenic mutations in non-small-cell lung cancer. In-frame deletions in this region (exon 19, codons 746-759) are recurrently described as gain-of-function alterations in the literature. The variant removes the conserved LREA motif (codons 747-750), known to be critical for kinase regulation.	PMID:15710947 PMID:15329413 PMID:15118073 PMID:15118125
PM2	Met	The variant is absent from all population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, consistent with a rare variant not observed in the general population (allele frequency <0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per instruction.
PM4	Met	The variant is an in-frame deletion of 7 amino acids (E746-S752) with insertion of a single valine residue within the EGFR kinase domain. This protein length change occurs in a non-repeat region and removes critical residues of the ATP-binding pocket. In-frame deletions in non-repeat regions are recognized as likely disruptive to protein structure and function per ACMG guidelines.	PMID:15710947 PMID:15329413 gnomad_v2 gnomad_v4
PM5	N/A	This is an in-frame deletion-insertion, not a missense variant. The automated PM5 candidate harvesting was unable to confirm classic same-residue missense semantics. PM5 is designed for novel missense changes at the same codon as a known pathogenic missense variant.
PM6	Not assessed	No data available regarding de novo occurrence. No parental testing reported in the reviewed literature.
PP1	Not assessed	No co-segregation data available. No family studies were identified in the literature review.
PP2	N/A	PP2 is specific to missense variants in genes with low rates of benign missense variation. This variant is an in-frame deletion-insertion, not a missense change.
PP3	N/A	In silico predictors (REVEL, BayesDel) are designed for single-nucleotide missense variants and are not applicable to this in-frame deletion-insertion. SpliceAI predicts no significant splice impact (max delta score 0.13). No applicable computational evidence is available for this variant type.	spliceai
PP4	Not assessed	No patient phenotype or family history data available. Germline clinical context is not provided in the case materials.
PP5	Not met	ClinVar classification for this variant (Variation ID 177652) is 'drug response' with review status 'no assertion criteria provided'. This does not constitute a reputable source reporting the variant as pathogenic. The ClinVar review status is 0 stars, which does not meet the PP5 threshold of 3-star expert panel classification. The ClinVar-submitted PMIDs (15118073, 15118125) do not contain the exact variant. None of the guideline papers cataloged under PP5 criteria index (PMID:23619274, 24627688, 29355391, 29398453, 34131312) were found to specifically reference NM_005228.4:c.2237_2255delinsT.	clinvar
BA1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. Allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation in healthy adult controls for a fully penetrant disorder. The variant is a well-known somatic oncogenic driver; germline control data are not available.
BS3	Not met	Functional studies demonstrate that this variant (and related EGFR exon 19 deletions) results in gain-of-function kinase activation, not loss of function. The variant is classified as Oncogenic with gain-of-function effect by OncoKB. In vitro data from Pao et al. 2004 (PMID:15329413) show exon 19 deletions alter EGFR phosphorylation and increase sensitivity to tyrosine kinase inhibitors, confirming a functional impact on the protein. The functional evidence does not show a benign or neutral effect.	PMID:15329413 PMID:15710947 oncokb
BS4	Not assessed	No segregation data available. No family studies identified for this variant.
BP1	N/A	BP1 is specific to missense variants in genes where primarily truncating variants cause disease. This is an in-frame deletion-insertion, not a missense variant.
BP2	Not assessed	No data available regarding observation in trans with a pathogenic variant.
BP3	Not met	The variant is an in-frame deletion-insertion in the EGFR tyrosine kinase domain, which is a well-characterized functional domain, not a repetitive region without known function. BP3 requires in-frame deletions to occur in repetitive regions.	PMID:15329413 PMID:15710947
BP4	Not met	While SpliceAI predicts no significant splice impact (max delta 0.13), multiple lines of functional and clinical evidence demonstrate this variant has a gain-of-function effect on EGFR kinase activity. The computed splicing neutrality does not outweigh the established functional impact of this in-frame deletion on protein function.	spliceai PMID:15329413 PMID:15710947 oncokb
BP5	Not assessed	No data available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6	Not met	ClinVar classification is 'drug response' (0 stars, no assertion criteria), not 'benign' or 'likely benign'. The ClinVar review status does not meet the 3-star expert panel threshold for BP6 application.	clinvar
BP7	N/A	Variant is an in-frame deletion-insertion altering the protein sequence, not a silent/synonymous variant with no predicted impact on splicing.

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