NM_005228.4:c.1372G>A

EGFR · NP_005219.2:p.(Asp458Asn) · NM_005228.4

GRCh37: chr7:55227905 G>A · GRCh38: chr7:55160212 G>A

Gene: EGFR Transcript: NM_005228.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

EGFR

Transcript

NM_005228.4

Protein

NP_005219.2:p.(Asp458Asn)

gnomAD AF

6.195149693402042e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 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).	pvs1_generic_framework
PS1	Not met	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.
PS2	Not met	No de novo evidence identified. No publication reports this variant as a confirmed de novo occurrence with both maternity and paternity confirmed.
PS3	Not assessed	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.	oncokb
PS4	Not met	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.	gnomad_v4
PS5	Not met	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.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to confirm classic same-residue PM5 semantics. No same-residue comparator variants identified in ClinVar with pathogenic classification. Automatic candidate harvesting returned zero candidates.
PM6	Not met	No de novo evidence identified. No publication reports this variant as occurring de novo, with or without maternity/paternity confirmation.
PP1	Not met	No segregation data available. No family studies or cosegregation analyses have been reported for this variant.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	No specific phenotypic or clinical presentation data available linking this variant to disease. No patient-level clinical information was provided in the case materials.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.	gnomad_v4
BS3	Not assessed	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.	oncokb
BS4	Not met	No evidence of non-segregation with disease; no family studies available for this variant.
BP1	Not met	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.
BP2	Not met	No evidence of this variant being observed in trans with a known pathogenic variant in EGFR or in a recessive condition.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease. No such clinical data were available for review.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.

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