NM_005228.4:c.2317_2318insCCCACCCCA (p.His773delinsProHisProAsn) is an in-frame insertion in exon 20 of EGFR, within the tyrosine kinase domain. This variant is absent from population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_supporting).1 The in-frame insertion in a non-repeat functional domain meets PM4 at moderate strength. No variant-specific functional studies were identified in five reviewed publications; OncoKB classifies the variant as Likely Oncogenic in a somatic context, but this does not independently satisfy germline PS3.2 The variant is absent from ClinVar; no expert panel or submitter classification is available.3 The variant is not in a statistically significant mutational hotspot per Cancer Hotspots analysis, and in silico splicing predictors (SpliceAI max delta 0.08) do not indicate a splice effect.4 Overall, 1 moderate criterion (PM4) and 1 supporting criterion (PM2) are met. This does not reach the threshold for Likely Pathogenic (requires ≥2 moderate + ≥2 supporting, ≥3 moderate, or 1 strong + ≥1 moderate). The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 criteria.5
EGFR
Final classification
VUS
PM2PM4
EGFR
c.2317_2318insCCCACCCCA
p.His773delinsProHisProAsn
This variant
NM_005228.4:c.2317_2318insCCCACCCCA (p.His773delinsProHisProAsn) is an in-frame insertion in exon 20 of EGFR, within the tyrosine kinase domain.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PM4 moderate; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PM2PM4
VUS
EGFR c.2317_2318insCCCACCCCA
PM2 + PM4
→
VUS
2
oncokb ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_005228.4 · variants mapped to exon structure
EGFR
NM_005228.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, supporting pathogenicity under PM2 (allele frequency <0.1% in population controls).
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0 (HostSeq genomes).
✓
PM4
moderate
Pathogenic
This variant is an in-frame insertion (p.His773delinsProHisProAsn) in exon 20 of EGFR, a non-repeat region encoding the tyrosine kinase domain. In-frame insertions/deletions in non-repeat regions meet PM4 at moderate strength.
In-frame insertion (net +3 amino acids) in EGFR tyrosine kinase domain (exon 20)a non-repeat functional region.
Assessed · not applied
· 10 not met · 9 not assessed
Pathogenic
PS2
No de novo data available for this variant.
PS3
No variant-specific functional studies were identified in the reviewed literature.
PS4
No case-control studies comparing variant prevalence in affected individuals versus controls are available.
PM1
Cancer Hotspots analysis indicates this residue is not a statistically significant mutational hotspot.
PM6
No de novo data (without confirmed maternity and paternity) are available for this variant.
PP1
No cosegregation data in affected family members are available for this variant.
PP3
SpliceAI predicts no significant splice impact (max delta score 0.08).
PP4
No patient phenotype or family history data are available to evaluate disease specificity.
PP5
This variant is absent from ClinVar; no reputable source has reported it as pathogenic.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No observation of this variant in a healthy adult individual for a fully penetrant disorder has been reported.
BS3
OncoKB classifies this variant as Likely Oncogenic with a gain-of-function biological effect.
BS4
No family segregation data are available to evaluate lack of cosegregation with disease.
BP2
No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder has been reported.
BP3
This is an in-frame insertion in the EGFR tyrosine kinase domain, a well-established functional domain, not a repetitive region without known function.
BP4
While SpliceAI predicts no splice impact (max delta 0.08), OncoKB classifies the variant as Likely Oncogenic with gain-of-function effect.
BP5
No data are available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6
This variant is absent from ClinVar; no reputable source has reported it as benign.
N/A · 7
PVS1 · PS1 · PM3 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
15897572 ↗
Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer.
ONCOKB
18676761 ↗
Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response.
ONCOKB
19536777 ↗
Second-line treatments after first-line gefitinib therapy in advanced nonsmall cell lung cancer.
ONCOKB
21764376 ↗
EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications.
ONCOKB