Variant classification summary

NM_005228.5:c.2303G>T

EGFR · NP_005219.2:p.(Ser768Ile) · NM_005228.5

GRCh37: chr7:55249005 G>T · GRCh38: chr7:55181312 G>T

Gene: EGFR Transcript: NM_005228.5

Final call

Likely Pathogenic

PS1 strong PM2 supporting PP3 supporting

Variant details

Gene

EGFR

Transcript

NM_005228.5

Protein

NP_005219.2:p.(Ser768Ile)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS1 strong is met for the previously reported EGFR p.Ser768Ile change.

2

Likely Pathogenic: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1.

3

Likely Pathogenic: PP3 supporting is met because REVEL is 0.765, above the 0.644 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 Strong pathogenic criterion plus 2 Supporting pathogenic criteria satisfies the Likely Pathogenic combination rule.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met: the exact EGFR p.Ser768Ile change was previously reported and ClinVar variation 45251 classifies it Pathogenic, with SpliceAI max delta 0.022.	clinvar PMID:15623594 PMID:23242437 spliceai
PS2	Not assessed	Not assessed: no documented proband-specific de novo result with both maternity and paternity confirmed and no family history.
PS3	Not assessed	Not assessed: tumor and treatment-response observations do not establish a validated, reproducible, robust assay for exact EGFR S768I functional damage.	PMID:15623594 PMID:23242437
PS4	Not assessed	Not assessed: S768I occurred in 2/101 tumors, but no control frequency was reported, so a valid OR and 95% CI could not be calculated.	PMID:15623594 gnomad_v2 gnomad_v4
PM1	Not assessed	Not assessed: residue 768 lies in EGFR's kinase domain, but no supplied evidence establishes absence of benign variation across that domain.	PMID:15623594 hotspots cosmic
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, meeting the PM2 frequency threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the evidence is from somatic EGFR tumors, with no recessive disorder or pathogenic variant demonstrated in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no verified different pathogenic missense substitution at EGFR Ser768 is supplied for comparison with p.Ser768I.	pm5_candidates PMID:15623594 PMID:23242437
PM6	Not assessed	Not assessed: no documented assumed de novo variant in a proband lacking confirmed maternity or paternity.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses with documented variant co-segregation are available.
PP2	Not assessed	Not assessed: the record lacks the gene-level benign missense rate and systematic evidence required for both PP2 conditions.	oncokb PMID:15623594 PMID:23242437
PP3	Met	Met at supporting: REVEL 0.765 meets the generic PP3 supporting threshold of >=0.644 for this missense variant.	revel
PP4	Not met	Not met: The reported phenotype is NSCLC, a heterogeneous cancer diagnosis rather than a phenotype highly specific to one genetic etiology.	PMID:15623594 PMID:23242437
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic classification; the available Pathogenic record is a single-submitter assertion.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no filtering allele frequency reaching the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: no gnomAD filtering allele frequency is available because the variant is absent, so it cannot exceed the BS1 default of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult carrier or genotype-defined cohort is available to evaluate the BS2 observation requirement.
BS3	Not assessed	Not assessed: no well-established controlled assay shows that exact EGFR S768I has no damaging effect on protein function or splicing.
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant or family non-segregation analysis are available.
BP1	Not met	Not met: available EGFR evidence centers on recurrent kinase-domain missense gain-of-function variants, not a disease mechanism primarily caused by truncating variants.	oncokb PMID:15623594 PMID:23242437
BP2	Not assessed	Not assessed: compound EGFR mutations were reported, but cis/trans phase and pathogenicity of the accompanying variant were not established.	PMID:15623594 PMID:23242437
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.765 exceeds the generic BP4 supporting cutoff of <=0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: The reports show additional EGFR alterations in some tumors but do not establish an alternate molecular basis for disease in the same case.	PMID:15623594 PMID:23242437
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign or likely-benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.