0%
EGFRc.2317_2318insCCCACCCCAUncertain significance
Print report
Variant interpretation report

EGFR c.2317_2318insCCCACCCCA, p.(His773delinsProHisProAsn)

NM_005228.4:c.2317_2318insCCCACCCCA NP_005219.2:p.(His773delinsProHisProAsn) View identifiers
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.

About EGFR

No gene-level summary was recorded for this case.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

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).

PM4Moderate
PM4 · moderate

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.

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: PM2 supporting, PM4 moderate; combination = 1 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.

SpliceAI score
0.080 maximum delta

Recorded SpliceAI maximum delta score: 0.080. 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: Gain-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 11 not met · 9 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

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.

The variant is absent from ClinVar; no expert panel or submitter classification is available.

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.

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.

Met · 2

PM2 SupportingThis 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). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PM4 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • In-frame insertion (net +3 amino acids) in EGFR tyrosine kinase domain (exon 20)
  • a non-repeat functional region.

Not met · 11 · evaluated, threshold not reached

PS3 No variant-specific functional studies were identified in the reviewed literature. OncoKB classifies this variant as Likely Oncogenic (gain-of-function) in a somatic cancer context, but this does not independently meet the threshold for germline PS3 functional evidence. Five peer-reviewed publications were reviewed in full text; none mention NM_005228.4:c.2317_2318insCCCACCCCA or its protein equivalents. Details ▾Hide ▴
Evidence considered
  • OncoKB curated classification: Likely Oncogenic
  • gain-of-function. No variant-specific functional assays (e.g.
  • kinase activity
  • cell proliferation
  • in vivo models) identified in reviewed literature.
Still missing
  • Variant-specific in vitro or in vivo functional studies are needed. OncoKB provides somatic oncogenicity annotation
  • not germline PS3-level evidence.
Sources
oncokb ↗
PM1 Cancer Hotspots analysis indicates this residue is not a statistically significant mutational hotspot. Although the variant lies within the EGFR tyrosine kinase domain (a critical functional domain), the residue-level hotspot metric is negative. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: 'This variant does not lie in a statistically significant hotspot.'
PP3 SpliceAI predicts no significant splice impact (max delta score 0.08). Standard in silico missense predictors (REVEL, BayesDel) are not applicable to in-frame insertions. No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.08 (well below the 0.2 threshold for splice prediction).
  • REVEL/BayesDel not applicable to non-SNV variants.
Sources
spliceai ↗
PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries for this variant.
Sources
clinvar ↗
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in all gnomAD datasets
  • does not reach BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in all gnomAD datasets
  • does not reach BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 OncoKB classifies this variant as Likely Oncogenic with a gain-of-function biological effect. Functional evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • OncoKB: Likely Oncogenic
  • gain-of-function. No evidence of normal protein function
  • available data suggest activating effect.
Sources
oncokb ↗
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. BP3 does not apply. Details ▾Hide ▴
Evidence considered
  • EGFR exon 20 encodes part of the tyrosine kinase domain
  • a critical functional region.
BP4 While SpliceAI predicts no splice impact (max delta 0.08), OncoKB classifies the variant as Likely Oncogenic with gain-of-function effect. The totality of evidence does not support multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.08 (no splicing impact predicted).
  • OncoKB Likely Oncogenic classification contradicts a benign computational interpretation.
Sources
spliceai ↗oncokb ↗
BP6 This variant is absent from ClinVar; no reputable source has reported it as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries for this variant.
Sources
clinvar ↗
PS5 This variant is absent from ClinVar; no reputable source has recently reported it as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries for this variant.
Sources
clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 No de novo data available for this variant. De novo occurrence with confirmed maternity and paternity has not been reported. Details ▾Hide ▴
Still missing
  • No proband or parental data available.
PS4 No case-control studies comparing variant prevalence in affected individuals versus controls are available. The variant is absent from gnomAD population controls but affected cohort data are lacking. Details ▾Hide ▴
Still missing
  • Case-control data needed to establish enrichment in affected individuals.
PM6 No de novo data (without confirmed maternity and paternity) are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo observation data available.
PP1 No cosegregation data in affected family members are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP4 No patient phenotype or family history data are available to evaluate disease specificity. Details ▾Hide ▴
Still missing
  • No proband phenotype data available.
BS2 No observation of this variant in a healthy adult individual for a fully penetrant disorder has been reported. Details ▾Hide ▴
Still missing
  • No healthy carrier data available.
BS4 No family segregation data are available to evaluate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP2 No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder has been reported. Details ▾Hide ▴
Still missing
  • No trans phase data available.
BP5 No data are available regarding an alternate molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data available.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is an in-frame insertion (p.His773delinsProHisProAsn), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus variant). The generic PVS1 framework does not apply. Details ▾Hide ▴
Evidence considered
  • Variant classified as 'other' by PVS1 bucket algorithm
  • not eligible for null-variant PVS1 scoring.
Sources
pvs1_generic_framework ↗
PS1 N/APS1 applies to missense variants with a previously established pathogenic variant at the same amino acid position. This is an in-frame insertion/deletion, not a missense change. Details ▾Hide ▴
Evidence considered
  • Not a missense variant
  • PS1 criterion semantics not applicable.
PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to novel missense variants at a residue where a different pathogenic missense change has been documented. This is an in-frame insertion/deletion, not a missense variant. The PM5 candidate search confirmed no eligible comparators. Details ▾Hide ▴
Evidence considered
  • PM5 candidate harvesting returned no eligible comparators
  • variant class is insertion
  • not missense.
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is an in-frame insertion, not a missense variant. Details ▾Hide ▴
Evidence considered
  • Not a missense variant
  • PP2 not applicable.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. This is an in-frame insertion, not a missense variant. Details ▾Hide ▴
Evidence considered
  • Not a missense variant
  • BP1 not applicable.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is an in-frame insertion, not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Not a synonymous variant
  • BP7 not applicable.

Identifiers

Gene
EGFR
Transcript
NM_005228.4
Coding (HGVS c.)
NM_005228.4:c.2317_2318insCCCACCCCA
Protein (HGVS p.)
NP_005219.2:p.(His773delinsProHisProAsn)
GRCh38
chr7:55181326 C>CCCCACCCCA
GRCh37
chr7:55249019 C>CCCCACCCCA

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…
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

SpliceAI acceptor lossat +329 bp
0.010
SpliceAI acceptor gainat -29 bp
0.080
SpliceAI donor lossat -150 bp
0.010
SpliceAI donor gainat +133 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts no significant splice impact (max delta score 0.08). Standard in silico missense predictors (REVEL, BayesDel) are not applicable to in-frame insertions. No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.08 (well below the 0.2 threshold for splice prediction).
  • REVEL/BayesDel not applicable to non-SNV variants.
Sources
spliceai ↗
BP4 While SpliceAI predicts no splice impact (max delta 0.08), OncoKB classifies the variant as Likely Oncogenic with gain-of-function effect. The totality of evidence does not support multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.08 (no splicing impact predicted).
  • OncoKB Likely Oncogenic classification contradicts a benign computational interpretation.
Sources
spliceai ↗oncokb ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is an in-frame insertion, not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Not a synonymous variant
  • BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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.
    This study examined EGFR mutations in exons 18-21 in 54 Taiwanese NSCLC patients receiving gefitinib. No duplication/insertion mutations were identified in exon 20. The variant NM_005228.4:c.2317_2318insCCCACCCCA was not reported.
    Does not name this variant
    PMID 15897572 ↗
    Quoted passage
    We identified one deletion mutation and four substitution mutations but no duplication/insertion mutations in exon 20.

    Results: Table 2 lists all EGFR mutations found. No exon 20 insertions/duplications identified (line 213: 'no duplication/insertion mutations in exon 20').

  • EGFR exon 20 insertion mutation in Japanese lung cancer.
    This study investigated EGFR exon 20 insertion mutations in 322 Japanese NSCLC patients. Seven exon 20 insertion mutations were identified, including 774_776insNPH (AACCCCCAC), 770_772insASV, 771_773insSVD, 772_773insV, and 772_773insN. NM_005228.4:c.2317_2318insCCCACCCCA (H773delinsPHPN) was not among the variants detected.
    Does not name this variant
    PMID 17686547 ↗
    Quoted passage
    Two female patients had 774 776 insertion NPH (2320-2328 insertion AACCCCCAC) mutations reported as D7 mutation by Shigematsu et al.

    Results section: seven exon 20 insertion mutations listed with nucleotide and protein descriptions. None correspond to the queried variant.

  • Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response.
    This study characterized EGFR exon 20 mutations in 23 NSCLC patients at National Taiwan University Hospital, evaluating gefitinib response. Reported exon 20 variants included S768I, R776G/H, G779S, T790M, K806E, A767_V769dupASV, S768_D770dupSVD, and D770_N771insD. NM_005228.4:c.2317_2318insCCCACCCCA was not identified.
    Does not name this variant
    PMID 18676761 ↗
    Quoted passage
    Mutations in exon 20 could be in-frame duplication and/or insertion, such as A767_V769dupASV or H773_V774insH.

    Table 2: complete listing of 23 exon 20 mutation patterns. No entry matches H773delinsPHPN.

  • Second-line treatments after first-line gefitinib therapy in advanced nonsmall cell lung cancer.
    This retrospective study examined second-line treatment outcomes after first-line gefitinib in 195 advanced NSCLC patients, including 61 with known EGFR mutations. EGFR mutation patterns listed in Table 2 include exon 19 deletions, L858R, and various exon 20 variants (A767_V769dupASV, H773Y + P772_H773insYNP), but NM_005228.4:c.2317_2318insCCCACCCCA was not among them.
    Does not name this variant
    PMID 19536777 ↗
    Quoted passage
    H773Y + P772_H773insYNP

    Table 2: EGFR mutations and their treatment responses. No match for the queried variant.

  • EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications.
    This comprehensive review catalogued 122 published EGFR exon 20 insertion mutations in NSCLC. His773-position insertions account for 14% of exon 20 insertions and include His773_Val774insAsnProHis, His773_Val774insHis, His773_Val774insProHis, His773_Val774insGlyAsnProHis, His773_Val774dupHisVal, His773_Val774insGly, and His773_Val774insGlyHis. NM_005228.4:c.2317_2318insCCCACCCCA (p.His773delinsProHisProAsn, which corresponds to His773_Val774insProHisProAsn in alternative nomenclature) was not listed among the compiled variants. However, the review confirms that His773-region insertions are a recognized class of EGFR exon 20 activating mutations that confer resistance to reversible and irreversible EGFR TKIs in preclinical models.
    Does not name this variant
    PMID 21764376 ↗
    Quoted passage
    His773_Val774insAsnProHis (6), His773_Val774insHis (3), His773_Val774insProHis (3), His773_Val774insGlyAsnProHis (2), His773_Val774dupHisVal (1), His773_Val774insGly (1), His773_Val774insGlyHis (1)

    Table 1 lists 17 His773_Val774 insertion variants; our specific variant is not among them. Figure 1B shows insertion distribution by residue.

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 0.080 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

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 = 0.08).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.