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.1 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.2 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.3 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.4
EGFR
Final classification
VUS
EGFR c.1372G>A · p.Asp458Asn
EGFR
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.
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.
Classification rationale
PM2
BP4
VUS
EGFR c.1372G>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
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 · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1.gnomAD v4.1: 1/1614
✓
BP4
supporting
Benign
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.
REVEL: 0.236 (benign-leaningbelow 0.5 threshold).BayesDel: -0.466 (benign prediction).
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 458 that is known to be pathogenic.
PS2
No de novo evidence identified.
PS3
No variant-specific functional studies identified.
PS4
No case-control or cohort evidence demonstrating enrichment of this variant in affected individuals.
PM1
The variant is not located in a statistically significant mutational hotspot.
PM6
No de novo evidence identified.
PP1
No segregation data available.
PP2
PP2 applies to genes with a low rate of benign missense variation where missense variants are a common mechanism of disease.
PP3
Multiple lines of in silico computational evidence do not support a pathogenic effect.
PP4
No specific phenotypic or clinical presentation data available linking this variant to disease.
PP5
ClinVar classification is Uncertain Significance (criteria provided, single submitter).
Benign
BA1
The variant allele frequency in gnomAD v4.1 is 0.00006% (1/1,614,166 alleles), well below the 1% (BA1) threshold.
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.
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.
BS3
No variant-specific functional studies demonstrating no damaging effect on protein function or splicing were identified.
BS4
No evidence of non-segregation with disease; no family studies available for this variant.
BP1
BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2
No evidence of this variant being observed in trans with a known pathogenic variant in EGFR or in a recessive condition.
BP5
No observation of this variant in a case with an alternate molecular basis for disease.
BP6
ClinVar classification is Uncertain Significance (not benign).
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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).
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
6.2e-05%
· 1 / 1,614,166
0 hom
0 hom
European (non-Finnish) 1 / 1,180,034 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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 = 0.09). REVEL score = 0.236. BayesDel score = -0.466321.
Functional
Unknown Oncogenic Effect
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.
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 · 6 PMIDs not cited in assessment
25311215 ↗
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.
CLINVAR
30813707 ↗
Provisional Guideline Recommendation for EGFR Gene Mutation Testing in Liquid Samples of Lung Cancer Patients: A Proposal by the Korean Cardiopulmonary Pathology Study Group.
CLINVAR
23667368 ↗
Guideline Recommendations for EGFR Mutation Testing in Lung Cancer: Proposal of the Korean Cardiopulmonary Pathology Study Group.
CLINVAR
24827857 ↗
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.
CLINVAR
25394175 ↗
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.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR