About EGFR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EGFR c.2314_2319dup, p.(Pro772_His773dup)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
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.
PM2Supporting
PM2 · supporting
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.
PM4Moderate
PM4 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
7 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV51810066, n = 7 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 9 not met · 7 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
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.
The variant is absent from ClinVar with no pathogenic or benign classifications from any submitter.
No criteria match.
Met · 3
PM1 ModerateThe 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. Details ▾Hide ▴
Evidence considered
- Located in EGFR tyrosine kinase domain (exon 20)
- a critical and well-established functional domain
- Exon 20 insertions/duplications are characterized as oncogenic gain-of-function mutations (PMID:24353160)
- OncoKB classifies as Likely Oncogenic
- Reported 7 times in COSMIC (COSV51810066)
- Absent from gnomAD v2.1 and v4.1
Sources
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles observed)
- Absent from gnomAD v4.1 (0 alleles observed)
Sources
PM4 ModerateNM_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. Details ▾Hide ▴
Evidence considered
- In-frame duplication of 2 amino acids (Pro772_His773) in EGFR kinase domain
- Variant is in a non-repeat
- functionally critical region
Sources
Not met · 9 · evaluated, threshold not reached
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). The generic PVS1 framework does not apply to this variant type. Details ▾Hide ▴
Evidence considered
- Variant classified as 'other' bucket by ClinGen PVS1 decision tree (PMC6185798)
- Variant is an in-frame duplication
- not a predicted null variant
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 This variant is absent from ClinVar and no pathogenic variant with the identical amino acid change (p.Pro772_His773dup) has been reported. There is no same-amino-acid comparator to satisfy PS1. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no known pathogenic variant with identical protein change
Sources
PS3 No variant-specific functional data are available for NM_005228.4:c.2314_2319dup (p.Pro772_His773dup). The sole functional paper reviewed (PMID:24353160) characterized other exon 20 insertion variants (Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD, H773_V774insH) but did not test or report this exact variant. OncoKB annotates this variant as Likely Oncogenic with Likely Gain-of-function, but curated database annotation alone does not constitute primary functional evidence for PS3 without variant-specific experimental data in the case folder. Details ▾Hide ▴
Evidence considered
- PMID:24353160 (Yasuda et al. 2013): characterized 6 exon 20 insertions showing gain-of-function but did not include p.Pro772_His773dup
- OncoKB classifies P772_H773dup as Likely Oncogenic / Likely Gain-of-function
- No variant-specific functional assay data identified
Still missing
- No variant-specific functional studies identified
- OncoKB annotation suggests gain-of-function but primary experimental data for this exact variant was not located
Sources
PP3 Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score 0.03). REVEL and BayesDel scores are unavailable for this non-SNV variant. No in silico tools predict a damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.03 — no predicted splicing impact
- REVEL and BayesDel not applicable (variant is non-SNV)
Still missing
- In silico missense prediction tools not applicable to in-frame duplications
Sources
PP5 This variant is absent from ClinVar. No reputable source has reported this variant as pathogenic. PP5 requires a reputable source (e.g., clinical diagnostic laboratory with appropriate quality control metrics) to have recently reported the variant as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar — no pathogenic classification from any submitter
Sources
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. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% in gnomAD (threshold for BA1 is >1%)
Sources
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. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% in gnomAD (threshold for BS1 is >0.3%)
Sources
BS3 No well-established functional studies show a neutral or benign effect for this variant. The only functional evidence reviewed (PMID:24353160) characterized exon 20 insertions as gain-of-function/activating, which is the opposite of a benign functional effect. OncoKB annotates this variant as Likely Oncogenic with Likely Gain-of-function. Details ▾Hide ▴
Evidence considered
- PMID:24353160: exon 20 insertions characterized as gain-of-function
- not neutral/benign
- OncoKB: Likely Oncogenic
- Likely Gain-of-function
Sources
BP4 Multiple lines of computational evidence are required to suggest no impact on the gene product. The only available computational data is SpliceAI (max delta 0.03, no predicted splicing impact). REVEL and BayesDel are unavailable for this non-SNV variant. A single computational tool is insufficient to satisfy the 'multiple lines of evidence' requirement for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.03 — no significant splice impact
- Only one line of computational evidence available
- insufficient for BP4
Sources
Not assessed · 7 · no assessment recorded
PS2 No de novo data available for this variant. No parental testing or trio analysis reported in any reviewed source. Details ▾Hide ▴
Still missing
- No de novo or trio data available
PS4 No case-control or prevalence data available for this variant in the germline setting. Details ▾Hide ▴
Still missing
- No case-control or cohort prevalence data
PM6 No de novo data available for this variant. No confirmed de novo occurrence reported in any reviewed source. Details ▾Hide ▴
Still missing
- No de novo or maternity/paternity confirmation data
PP1 No segregation data available for this variant. No family studies or cosegregation analyses were identified. Details ▾Hide ▴
Still missing
- No family segregation data
PP4 No patient phenotype or clinical data were provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene. Details ▾Hide ▴
Still missing
- No patient phenotype data provided
BS2 No data available on observation of this variant in healthy adults. BS2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in an autosomal recessive disorder, or in homozygous state for a dominant disorder in unaffected individuals. Details ▾Hide ▴
Still missing
- No population or clinical data on variant observation in healthy individuals
BS4 No segregation data available for this variant. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ASkipped per case instructions. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a novel missense change at an amino acid residue where a different missense change has been established as pathogenic. This variant is an in-frame duplication, not a missense substitution. No same-residue comparator variants were identified in the PM5 candidate search. PM5 semantics cannot be applied to this variant class. Details ▾Hide ▴
Evidence considered
- Variant is in-frame duplication
- not missense
- PM5 candidate search returned 0 same-residue comparators
Sources
pm5_candidates
PP2 N/APP2 specifically applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_005228.4:c.2314_2319dup is an in-frame duplication, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_005228.4:c.2314_2319dup is an in-frame duplication, not a missense variant. Additionally, EGFR disease mechanisms include both gain-of-function (oncogenic) and loss-of-function contexts. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ABP2 requires observation of the variant in trans with a known pathogenic dominant variant, or in cis with a pathogenic recessive variant. No such data are available or relevant to this case. The variant is absent from population databases making this criterion inapplicable. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. The p.Pro772_His773dup variant is located in exon 20 of the EGFR tyrosine kinase domain, which is neither a repetitive region nor without known function. The EGFR kinase domain is one of the most well-characterized functional domains in oncology. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ABP5 requires an alternate molecular basis for disease to have been identified in the case. No case-level data (phenotype, alternate genetic findings) were provided. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 requires a reputable source to have recently reported the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. This variant is absent from ClinVar; no benign classification exists from any source. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar — no benign classification available
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or a new splice site, and the nucleotide is not highly conserved. NM_005228.4:c.2314_2319dup is an in-frame duplication, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 requires a known pathogenic variant at the same amino acid residue. This is an in-frame duplication (not a missense change), and no comparator pathogenic variants were identified at residues 772-773. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- EGFR
- Transcript
- NM_005228.4
- Coding (HGVS c.)
- NM_005228.4:c.2314_2319dup
- Protein (HGVS p.)
- NP_005219.2:p.(Pro772_His773dup)
- GRCh38
- chr7:55181320 A>AACCCCC
- GRCh37
- chr7:55249013 A>AACCCCC
- COSMIC
- COSV51810066
Gene diagram
Every interpreted variant in EGFR, mapped onto the exon structure of NM_005228.4. Select a row to find it on the plot.
EGFRNM_005228.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in EGFR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score 0.03). REVEL and BayesDel scores are unavailable for this non-SNV variant. No in silico tools predict a damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.03 — no predicted splicing impact
- REVEL and BayesDel not applicable (variant is non-SNV)
Still missing
- In silico missense prediction tools not applicable to in-frame duplications
Sources
BP4 Multiple lines of computational evidence are required to suggest no impact on the gene product. The only available computational data is SpliceAI (max delta 0.03, no predicted splicing impact). REVEL and BayesDel are unavailable for this non-SNV variant. A single computational tool is insufficient to satisfy the 'multiple lines of evidence' requirement for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.03 — no significant splice impact
- Only one line of computational evidence available
- insufficient for BP4
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or a new splice site, and the nucleotide is not highly conserved. NM_005228.4:c.2314_2319dup is an in-frame duplication, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
1 paper record listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
-
PMID 24353160 ↗Structural, biochemical, and clinical characterization of epidermal growth factoCharacterized 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.→ PM1 Does not name this variant
Source detail
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
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005228.4%3Ac.2314_2319dup
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-55249013-A-AACCCCC?dataset=…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-55181320-A-AACCCCC?datas…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-55181320-A-AACCCCC
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005228.4%3Ac.2314…
- OncoKB ↗www.oncokb.org/gene/EGFR/P772_H773dup
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120717197
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51810066, n = 7 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.