0%
EGFRc.1372G>AUncertain significance
Print report
Variant interpretation report

EGFR c.1372G>A, p.(Asp458Asn)

NM_005228.4:c.1372G>A NP_005219.2:p.(Asp458Asn) 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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

The variant is absent from gnomAD v2.1 and is present at an extremely low frequency in gnomAD v4.1 (1/1,614,166 alleles, AF=6.2×10⁻⁷, approximately 0.00006%), with no homozygotes observed. This is well below the 0.1% threshold for PM2. Also absent from gnomAD-Canada v1.0.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of in silico computational evidence predict a benign effect. REVEL score is 0.236 (benign leaning), BayesDel score is -0.466 (benign prediction), and SpliceAI max delta is 0.09 (no predicted splicing impact). All three in silico tools consistently predict a benign or tolerated effect.

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, BP4 supporting; combination = 1 supporting + 1 supporting benign, 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
0.090 maximum delta

Recorded SpliceAI maximum delta score: 0.090. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EGFR, a receptor tyrosine kinase, is altered by amplification and/or mutation in lung and brain cancers among others.

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.

26 criteria with recorded statuses: 2 met · 19 not met · 2 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,614,166 alleles, AF=0.00006%), meeting PM2 at supporting level.

Multiple in silico tools consistently predict a benign effect: REVEL score 0.236, BayesDel score -0.466, and SpliceAI max delta 0.09 (no splicing impact). This meets BP4 at supporting level.

The ClinVar record (Variation ID 953833) matched to NM_005228.5:c.1507G>A (p.Gly503Ser), a different variant on a different transcript version. Two clinical laboratories classify as VUS. None of the ten ClinVar-associated PMIDs mention NM_005228.4:c.1372G>A specifically; all are general EGFR testing or cancer referral guidelines.

Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in conflicting evidence. Without additional functional, segregation, or case-control data, this variant remains a Variant of Uncertain Significance per generic ACMG/AMP 2015 rules.

Met · 2

PM2 SupportingThe variant is absent from gnomAD v2.1 and is present at an extremely low frequency in gnomAD v4.1 (1/1,614,166 alleles, AF=6.2×10⁻⁷, approximately 0.00006%), with no homozygotes observed. This is well below the 0.1% threshold for PM2. Also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • gnomAD v4.1: 1/1
  • 614
  • 166 alleles (AF=0.00006%)
  • 0 homozygotes.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of in silico computational evidence predict a benign effect. REVEL score is 0.236 (benign leaning), BayesDel score is -0.466 (benign prediction), and SpliceAI max delta is 0.09 (no predicted splicing impact). All three in silico tools consistently predict a benign or tolerated effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.236 (benign-leaning
  • below 0.5 threshold).
  • BayesDel: -0.466 (benign prediction).
  • SpliceAI: max delta 0.09 (no splicing impact predicted).
Sources
revelbayesdelspliceai ↗

Not met · 19 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at codon 458 that is known to be pathogenic. No same-codon comparator variants identified in ClinVar or the literature. Details ▾Hide ▴
Still missing
  • No same-codon pathogenic comparators identified.
PS2 No de novo evidence identified. No publication reports this variant as a confirmed de novo occurrence with both maternity and paternity confirmed. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PS4 No case-control or cohort evidence demonstrating enrichment of this variant in affected individuals. The variant is extremely rare (1/1,614,166 alleles in gnomAD v4.1). No published case series or controlled studies have reported this variant in affected individuals at a statistically significant rate. Details ▾Hide ▴
Evidence considered
  • Extremely rare in population (1 allele in gnomAD v4.1
  • AF=0.00006%). No case-control data.
Still missing
  • No case-control studies or cohort enrichment data available.
Sources
gnomad_v4 ↗
PM1 The variant is not located in a statistically significant mutational hotspot. Hotspots analysis found no enrichment at this residue. Additionally, there is insufficient evidence that the extracellular domain region at residue 458 is a well-established critical functional domain with complete absence of benign variation. Details ▾Hide ▴
Evidence considered
  • Hotspots analysis: residue not significant
  • exact variant not listed.
Still missing
  • No domain-level constraint data specific to EGFR codon 458 in germline context.
PM6 No de novo evidence identified. No publication reports this variant as occurring de novo, with or without maternity/paternity confirmation. Details ▾Hide ▴
Evidence considered
  • No de novo reports for this variant in any reviewed source.
Still missing
  • No de novo testing data.
PP1 No segregation data available. No family studies or cosegregation analyses have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies or cosegregation data.
PP2 PP2 applies to genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. While EGFR harbors pathogenic missense variants in somatic (lung cancer) context, there is insufficient evidence that EGFR meets the PP2 gene threshold for germline disease. The gene has not been established as having a low rate of benign missense variation in the germline context. Details ▾Hide ▴
Evidence considered
  • EGFR not established as a low-benign-missense-rate gene in the germline context.
PP3 Multiple lines of in silico computational evidence do not support a pathogenic effect. REVEL score is 0.236 (below the 0.5 threshold), BayesDel score is -0.466 (negative, predicting benign), and SpliceAI max delta is 0.09 (no predicted splicing impact). All three in silico tools are consistent with a benign or tolerated prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.236 (below 0.5 pathogenic threshold).
  • BayesDel: -0.466 (benign prediction).
  • SpliceAI: max delta 0.09 (no splicing impact).
Sources
revelbayesdelspliceai ↗
PP4 No specific phenotypic or clinical presentation data available linking this variant to disease. No patient-level clinical information was provided in the case materials. Details ▾Hide ▴
Evidence considered
  • No patient-specific phenotype data available.
Still missing
  • No patient phenotype information provided for assessment.
PP5 ClinVar classification is Uncertain Significance (criteria provided, single submitter). Notably, the ClinVar record (Variation ID 953833) matched to NM_005228.5:c.1507G>A (p.Gly503Ser), a different variant on a different transcript version, not NM_005228.4:c.1372G>A (p.Asp458Asn). No reputable source has classified this specific variant as pathogenic. The ClinVar-associated PMIDs are general EGFR testing guidelines that do not mention this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS (2 submitters)
  • matched to a different variant (NM_005228.5:c.1507G>A).
  • No reputable source classifies this variant as pathogenic.
Still missing
  • No authoritative classification from an expert panel or reputable source.
Sources
clinvar ↗
BA1 The variant allele frequency in gnomAD v4.1 is 0.00006% (1/1,614,166 alleles), well below the 1% (BA1) threshold. It is also absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: AF=0.00006%
  • far below BA1 threshold of 1%.
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant allele frequency in gnomAD v4.1 is 0.00006% (1/1,614,166 alleles), well below the 0.3% (BS1) threshold for a rare disease. It is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: AF=0.00006%
  • far below BS1 threshold of 0.3%.
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 The variant has been observed in only 1 of 1,614,166 alleles in gnomAD v4.1, which is insufficient to meet the requirement for observation in a healthy adult at significant frequency. No additional observation of this variant in unaffected individuals with full penetrance data is available. Details ▾Hide ▴
Evidence considered
  • Only 1 allele in gnomAD v4.1
  • insufficient for BS2.
Sources
gnomad_v4 ↗
BS4 No evidence of non-segregation with disease; no family studies available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation or non-segregation data available.
Still missing
  • No segregation data.
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. While truncating EGFR variants have been associated with disease, pathogenic missense variants are also established in EGFR, particularly in the tyrosine kinase domain. Thus, BP1 does not apply cleanly to this gene in the germline context. Details ▾Hide ▴
Evidence considered
  • EGFR has both truncating and missense pathogenic variants
  • BP1 does not cleanly apply.
BP2 No evidence of this variant being observed in trans with a known pathogenic variant in EGFR or in a recessive condition. Details ▾Hide ▴
Evidence considered
  • No observation in trans with a pathogenic variant.
Still missing
  • No phasing data available.
BP5 No observation of this variant in a case with an alternate molecular basis for disease. No such clinical data were available for review. Details ▾Hide ▴
Evidence considered
  • No case with alternate molecular basis identified.
Still missing
  • No clinical case data available.
BP6 ClinVar classification is Uncertain Significance (not benign). Additionally, the ClinVar record matched is for a different variant (NM_005228.5:c.1507G>A) and would not constitute a valid BP6 source for this variant even if benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS. No reputable source classifies as benign or likely benign.
Sources
clinvar ↗
PS5 PS5 pertains to a variant found to be de novo but with maternity/paternity not confirmed. No de novo evidence of any kind was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo evidence of any kind identified.
Still missing
  • No de novo observation data.

Not assessed · 2 · no assessment recorded

PS3 No variant-specific functional studies identified. OncoKB classification is 'Unknown Oncogenic Effect' with no reviewed functional evidence for this variant. No published functional data found in the literature reviewed. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect. No variant-specific functional data available.
Still missing
  • No functional studies (in vitro or in vivo) identified for p.Asp458Asn.
Sources
oncokb ↗
BS3 No variant-specific functional studies demonstrating no damaging effect on protein function or splicing were identified. OncoKB reports 'Unknown Oncogenic Effect' and no reviewed functional evidence is available for this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect. No functional studies available.
Still missing
  • No functional studies (in vitro or in vivo) assessing the effect of p.Asp458Asn on protein function or splicing.
Sources
oncokb ↗
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_005228.4:c.1372G>A is a missense substitution (p.Asp458Asn) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant eligible for PVS1 per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_generic_framework ↗
PM5 N/AUnable to confirm classic same-residue PM5 semantics. No same-residue comparator variants identified in ClinVar with pathogenic classification. Automatic candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variants identified.
Still missing
  • No ClinVar entries at EGFR codon 458 with confirmed pathogenic classification.
BP7 N/ABP7 applies to synonymous variants where splicing is not predicted to be affected. NM_005228.4:c.1372G>A is a missense variant (p.Asp458Asn), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Identifiers

Gene
EGFR
Transcript
NM_005228.4
Coding (HGVS c.)
NM_005228.4:c.1372G>A
Protein (HGVS p.)
NP_005219.2:p.(Asp458Asn)
GRCh38
chr7:55160212 G>A
GRCh37
chr7:55227905 G>A
ClinVar
953833

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 1 / 1,614,166 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,166 alleles · 0 hom
European (non-Finnish)1 / 1,180,034 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19515e-07; MAF= 0.00006%, 1/1614166 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47433e-07; MAF= 0.00008%, 1/1180034 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -73 bp
0.090
SpliceAI acceptor gainat +22 bp
0.040
SpliceAI donor lossat +126 bp
0.060
SpliceAI donor gainat -3 bp
0.000
Pangolin splice lossmagnitude shown
-0.090
Pangolin splice gain
0.030

Other predictors

REVEL
0.236
BayesDel
-0.466

How the predictions were used

BP4 SupportingMultiple lines of in silico computational evidence predict a benign effect. REVEL score is 0.236 (benign leaning), BayesDel score is -0.466 (benign prediction), and SpliceAI max delta is 0.09 (no predicted splicing impact). All three in silico tools consistently predict a benign or tolerated effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.236 (benign-leaning
  • below 0.5 threshold).
  • BayesDel: -0.466 (benign prediction).
  • SpliceAI: max delta 0.09 (no splicing impact predicted).
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of in silico computational evidence do not support a pathogenic effect. REVEL score is 0.236 (below the 0.5 threshold), BayesDel score is -0.466 (negative, predicting benign), and SpliceAI max delta is 0.09 (no predicted splicing impact). All three in silico tools are consistent with a benign or tolerated prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.236 (below 0.5 pathogenic threshold).
  • BayesDel: -0.466 (benign prediction).
  • SpliceAI: max delta 0.09 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants where splicing is not predicted to be affected. NM_005228.4:c.1372G>A is a missense variant (p.Asp458Asn), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.236. BayesDel score = -0.466321.

6 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

  • Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cancer/association for molecular pathology guideline.
    Leighl NB et al. · 2014
    ASCO endorsement of CAP/IASLC/AMP guideline on molecular testing for EGFR and ALK tyrosine kinase inhibitors in lung cancer. Discusses EGFR mutation testing at a general guideline level. NM_005228.4:c.1372G>A was not identified in this paper.
    Does not name this variant
    PMID 25311215 ↗
    Quoted passage
    The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) guideline on molecular testing for the selection of patients with lung cancer for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors was considered for endorsement.
  • Provisional Guideline Recommendation for EGFR Gene Mutation Testing in Liquid Samples of Lung Cancer Patients: A Proposal by the Korean Cardiopulmonary Pathology Study Group.
    Shin DH et al. · 2019
    Provisional guideline recommendation by the Korean Cardiopulmonary Pathology Study Group for EGFR mutation testing in liquid samples of lung cancer patients. Discusses testing methodology for common EGFR mutations (exon 19 deletions, T790M, L858R, etc.) in circulating tumor DNA. NM_005228.4:c.1372G>A was not identified in this paper.
    Does not name this variant
    PMID 30813707 ↗
  • Guideline Recommendations for EGFR Mutation Testing in Lung Cancer: Proposal of the Korean Cardiopulmonary Pathology Study Group.
    Shim HS et al. · 2013
    Guideline recommendations by the Korean Cardiopulmonary Pathology Study Group for EGFR mutation testing in lung cancer. Provides general testing methodology recommendations for common EGFR activating mutations. NM_005228.4:c.1372G>A was not identified in this paper.
    Does not name this variant
    PMID 23667368 ↗
  • Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer: a systematic review and cost-effectiveness analysis.
    Westwood M et al. · 2014
    Systematic review and cost-effectiveness analysis of EGFR-TK mutation testing in adults with advanced or metastatic NSCLC. Evaluates testing strategies for known EGFR driver mutations at a health-technology-assessment level. NM_005228.4:c.1372G>A was not identified in this paper.
    Does not name this variant
    PMID 24827857 ↗
    Quoted passage
    Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours responsive to treatment with EGFR-TK inhibitors (EGFR-TKIs) but less responsive to treatment with standard chemotherapy.
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. Lists criteria for referral to cancer genetic consultation for known hereditary cancer syndromes. NM_005228.4:c.1372G>A was not identified in this paper; EGFR is not listed among the syndromes covered.
    Does not name this variant
    PMID 25394175 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc refinement of ACMG-AMP variant classification criteria. Provides a comprehensive framework for variant interpretation. NM_005228.4:c.1372G>A was not identified in this paper; it is a methods paper, not a variant-specific report.
    Does not name this variant
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,614,166 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.090 Open source ↗
ClinVar 2 Uncertain significance 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

This variant is present in gnomAD v4.1 (AF= 6.19515e-07; MAF= 0.00006%, 1/1614166 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47433e-07; MAF= 0.00008%, 1/1180034 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

Error retrieving ClinVar entry.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.236. BayesDel score = -0.466321.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EGFR, a receptor tyrosine kinase, is altered by amplification and/or mutation in lung and brain cancers among others.

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.