NM_005228.4:c.2314_2319dup (p.Pro772_His773dup) is an in-frame duplication in exon 20 of the EGFR tyrosine kinase domain, a critical functional domain where exon 20 insertions and duplications are established oncogenic gain-of-function mutations.1 This variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles observed), consistent with a rare variant not present in the general population.2 The variant has been reported 7 times in somatic cancers (COSMIC COSV51810066) and is classified as Likely Oncogenic with Likely Gain-of-function by OncoKB.3 No variant-specific functional studies were identified in the literature. The sole functional paper reviewed (PMID:24353160) characterized six other EGFR exon 20 insertion variants but did not include p.Pro772_His773dup.4 SpliceAI predicts no significant splicing impact for this variant (max delta score 0.03). REVEL and BayesDel scores are not available for this non-SNV variant.5 The variant is absent from ClinVar with no pathogenic or benign classifications from any submitter.6
EGFR
Final classification
VUS
EGFR c.2314_2319dup · p.Pro772_His773dup
EGFR
NM_005228.4:c.2314_2319dup (p.Pro772_His773dup) is an in-frame duplication in exon 20 of the EGFR tyrosine kinase domain, a critical functional domain where exon 20 insertions and duplications are established oncogenic gain-of-function mutations.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, PM4 moderate; combination = 2 moderate + 1 supporting, which maps to VUS.
Classification rationale
PM1PM2PM4
VUS
EGFR c.2314_2319dup
PM1 + PM2 + PM4
→
VUS
Gene diagram
· NM_005228.4 · variants mapped to exon structure
EGFR
NM_005228.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 16 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
The variant p.Pro772_His773dup is located in exon 20 of EGFR, within the N-lobe of the tyrosine kinase domain (C-helix region, residues 762–774). Exon 20 of EGFR is a well-established mutational hotspot and critical functional domain where in-frame insertions and duplications are known to be oncogenic (Yasuda et al. 2013, PMID:24353160). The variant is absent from population databases, consistent with the 'without benign variation' requirement.
Located in EGFR tyrosine kinase domain (exon 20)a critical and well-established functional domainExon 20 insertions/duplications are characterized as oncogenic gain-of-function mutations (PMID:24353160)
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), consistent with a rare variant not observed in population databases. Under generic ACMG/AMP 2015 rules, allele frequency below 0.1% supports PM2.
Absent from gnomAD v2.1 (0 alleles observed)Absent from gnomAD v4.1 (0 alleles observed)
✓
PM4
moderate
Pathogenic
NM_005228.4:c.2314_2319dup is a 6-nucleotide in-frame duplication resulting in the insertion of two amino acids (Pro772_His773dup) within exon 20 of the EGFR kinase domain, which is not a repetitive region. This protein length alteration due to in-frame duplication in a non-repeat region satisfies PM4 under generic ACMG/AMP 2015.
In-frame duplication of 2 amino acids (Pro772_His773) in EGFR kinase domainVariant is in a non-repeatfunctionally critical region
Assessed · not applied
Pathogenic
PVS1
NM_005228.4:c.2314_2319dup is an in-frame duplication in exon 20 that does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants).
PS1
This variant is absent from ClinVar and no pathogenic variant with the identical amino acid change (p.Pro772_His773dup) has been reported.
PS2
No de novo data available for this variant.
PS3
No variant-specific functional data are available for NM_005228.4:c.2314_2319dup (p.Pro772_His773dup).
PS4
No case-control or prevalence data available for this variant in the germline setting.
PM6
No de novo data available for this variant.
PP1
No segregation data available for this variant.
PP3
Computational evidence does not support a deleterious effect.
PP4
No patient phenotype or clinical data were provided for this case.
PP5
This variant is absent from ClinVar.
Benign
BA1
This variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0%, far below the BA1 threshold of >1% in population databases.
BS1
This variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0%, far below the BS1 threshold of >0.3% in population databases.
BS2
No data available on observation of this variant in healthy adults.
BS3
No well-established functional studies show a neutral or benign effect for this variant.
BS4
No segregation data available for this variant.
BP4
Multiple lines of computational evidence are required to suggest no impact on the gene product.
N/A · 9
PM3 · PM5 · PP2 · BP1 · BP2 · BP3 · BP5 · BP6 · 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 = 0.03).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely 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 previously been reported in somatic cancers (COSMIC; COSV51810066, n = 7 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Structural, biochemical, and clinical characterization of epidermal growth facto
Searched
c.2314_2319dupp.Pro772_His773dupP772_H773dupPro772His773772_7732314insPH
Found
Characterized six EGFR exon 20 insertion mutations (Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD, H773_V774insH) in non-small-cell lung cancer. All tested exon 20 insertions were activating (gain-of-function) and conferred resistance to first-generation EGFR tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib. NM_005228.4:c.2314_2319dup (p.Pro772_His773dup) was not among the variants tested or reported in this study. A related variant, H773_V774insH (annotated as identical to P772_H773insH), was characterized.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
Why
Variant not tested in this study. Paper provides domain-level evidence that EGFR exon 20 insertions are activating oncogenic mutations within a critical functional domain, supporting PM1. Cited for BS3 as evidence against a benign functional effect (exon 20 insertions characterized as gain-of-function).
H773_V774insH [identical to P772_H773insH]
Location Sup. Table 1; Results describing characterized exon 20 insertion panel · Context Ba/F3 cell models, NIH-3T3 cells; Western blot for EGFR, p-EGFR, p-AKT, p-ERK; cell viability assays with gefitinib, erlotinib, afatinib; X-ray crystallography of EGFR T790M kinase domain with D770_N771insNPG peptide · full text
Sources & reference links