Variant classification summary

NM_005228.4:c.2317_2319dupCAC

EGFR · NP_005219.2:p.(His773dup) · NM_005228.4

GRCh37: chr7:55249017 C>CCCA · GRCh38: chr7:55181324 C>CCCA

Gene: EGFR Transcript: NM_005228.4

Final call

Likely Pathogenic

PM1 moderate PM2 moderate PM4 moderate

Variant details

Gene

EGFR

Transcript

NM_005228.4

Protein

NP_005219.2:p.(His773dup)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_005228.4:c.2317_2319dupCAC (p.His773dup) is an in-frame duplication in exon 20 of EGFR, located in the tyrosine kinase domain C-helix/post-C-helix region, a critical functional domain (PM1).

2

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).

3

The in-frame duplication results in a protein length change (p.His773dup) in a non-repeat region of EGFR (PM4).

4

ClinVar classifies this variant as Uncertain significance (Variation ID 45261, 0-star review status) based on a single clinical laboratory submission with no assertion criteria provided.

5

OncoKB annotates this variant as Likely Oncogenic with gain-of-function biological effect. COSMIC reports 15 somatic observations (COSV51781591), consistent with a role in tumorigenesis.

6

No variant-specific functional studies were identified for p.His773dup in the reviewed literature. Sister exon 20 insertion variants at His773 (His773_Val774insHis) have been characterized as conferring EGFR TKI resistance in vitro, but the exact variant has not been experimentally tested.

7

SpliceAI predicts no splice alteration (max delta = 0.00). REVEL and BayesDel are not applicable to this variant type.

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	NM_005228.4:c.2317_2319dup is an in-frame duplication (p.His773dup), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework explicitly excludes this variant bucket.	pvs1_generic_framework
PS1	N/A	PS1 applies to a nucleotide change producing the same amino acid change as a previously established pathogenic missense variant. This variant is an in-frame duplication (p.His773dup), not a missense substitution.
PS2	Not met	No de novo observation has been reported for NM_005228.4:c.2317_2319dupCAC (p.His773dup). None of the reviewed publications describe a de novo germline event for this variant.
PS3	Not met	No direct functional data exists for p.His773dup specifically. EGFR exon 20 insertions at nearby residues (His773_Val774insHis, Pro772_His773insAsn) have been characterized in vitro as conferring TKI resistance and gain-of-function, but the exact variant has not been experimentally tested. Variant-specific functional evidence is required for PS3; domain-level inference from sparse testing of sister variants does not satisfy PS3 thresholds.	PMID:21764376 PMID:18676761
PS4	Not met	No case-control data or statistically enriched observation of NM_005228.4:c.2317_2319dupCAC in affected individuals versus controls. COSMIC reports 15 somatic observations, but this represents somatic tumor profiling, not germline case-control data suitable for PS4.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion and no PS5 rule definition is provided in the case materials.
PM1	Met	p.His773dup is located in the EGFR tyrosine kinase domain, specifically in exon 20 within the C-helix/post-C-helix region (residues 762–823). This is a well-characterized critical functional domain essential for kinase activity and ATP/drug binding. Exon 20 insertions in this region are established oncogenic drivers in NSCLC.	PMID:21764376 PMID:18676761 oncokb
PM2	Met	NM_005228.4:c.2317_2319dupCAC is absent from all population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP non-VCEP rules, absence from population databases meets PM2 at moderate strength (AF < 0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM4	Met	NM_005228.4:c.2317_2319dupCAC causes an in-frame duplication (p.His773dup), resulting in a protein length change by insertion of one amino acid in a non-repeat region of EGFR. PM4 applies to in-frame deletions/insertions in non-repeat regions.
PM5	N/A	PM5 applies to a different missense change at the same codon as an established pathogenic variant. This variant is an in-frame duplication (p.His773dup), not a missense substitution. The PM5 candidate collector was unable to confirm classic same-residue PM5 semantics for this variant type.	pm5_candidates
PM6	Not met	No de novo observation has been reported for NM_005228.4:c.2317_2319dupCAC in any of the reviewed publications. PM6 requires confirmed de novo status.
PP1	Not met	No cosegregation data is available for NM_005228.4:c.2317_2319dupCAC. PP1 requires evidence of segregation with disease in affected family members.
PP2	N/A	PP2 applies to missense variants in a gene with a low rate of benign missense variation. This variant is an in-frame duplication, not a missense substitution.
PP3	Not met	In silico predictors provide no evidence supporting pathogenicity. SpliceAI max delta score is 0.00 (no splice impact). REVEL and BayesDel scores are unavailable (not a single nucleotide substitution). HCI prior is not available for EGFR. No computational evidence supports a deleterious effect.	spliceai
PP4	Not assessed	No patient phenotype information is available to evaluate specificity of the patient's clinical presentation for EGFR-related disease.
PP5	Not met	ClinVar classifies this variant as Uncertain significance (Variation ID 45261) with review status 'no assertion criteria provided' (0 stars) by a single clinical laboratory. PP5 requires a reputable source (≥3-star expert panel) to have classified the variant as pathogenic. This 0-star VUS classification does not meet PP5 threshold.	clinvar
BA1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). BA1 requires an allele frequency >1% in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from all population databases. BS1 requires an allele frequency >0.3% under generic ACMG non-VCEP rules.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adult controls (homozygous or heterozygous) is available.
BS3	Not met	Available evidence suggests gain-of-function, not benign effect. OncoKB classifies this variant as Likely Oncogenic with gain-of-function biological effect. Sister exon 20 insertion variants at His773 (His773_Val774insHis) have been shown to confer TKI resistance in vitro. No functional data support a benign or neutral effect for this variant or its region.	oncokb PMID:21764376
BS4	Not assessed	No segregation data is available to evaluate lack of cosegregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is an in-frame duplication, not a missense substitution.
BP2	Not assessed	No data available on whether this variant has been observed in trans with a known pathogenic variant in EGFR.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. While this is an in-frame duplication, the EGFR exon 20 C-helix region is a well-characterized functional domain, not a repetitive region of unknown significance.	PMID:21764376
BP4	Not met	No in silico evidence supports a benign effect. SpliceAI predicts no splice alteration (delta = 0.00), which is neutral but not positively benign. REVEL/BayesDel are not applicable to duplication variants. No multiple lines of computational evidence suggest no impact.	spliceai
BP5	Not assessed	No data available on whether an alternate molecular basis for disease has been identified in the proband.
BP6	Not met	ClinVar classifies this variant as Uncertain significance (Variation ID 45261) with review status 'no assertion criteria provided' (0 stars). BP6 requires a reputable source (≥3-star expert panel) to have classified the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_005228.4:c.2317_2319dupCAC is an in-frame duplication causing p.His773dup, not a synonymous variant.

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