Variant classification summary

NM_005228.5:c.2582T>A

EGFR · NP_005219.2:p.(Leu861Gln) · NM_005228.5

GRCh37: chr7:55259524 T>A · GRCh38: chr7:55191831 T>A

Gene: EGFR Transcript: NM_005228.5

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

EGFR

Transcript

NM_005228.5

Protein

NP_005219.2:p.(Leu861Gln)

gnomAD AF

ClinVar

drug response

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: L861Q showed transforming, tumorigenic, signaling, and drug-response effects in multiple functional assays.

2

PM1 moderate: L861 is in the EGFR tyrosine-kinase domain and a significant mutational hotspot.

3

PM2 supporting: the variant was absent from gnomAD v2.1, v4.1, and reported non-cancer subsets.

4

PP3 supporting: REVEL 0.864 exceeds the generic supporting threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one or two moderate criteria supports Likely Pathogenic; this case has PS3 strong and PM1 moderate, with PM2 and PP3 supporting.

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	Not assessed	Not assessed: L861Q is reported, but no independently established pathogenic variant with the same amino-acid change and a different nucleotide change was documented.	clinvar PMID:15118073 PMID:17177598
PS2	Not assessed	Not assessed: the variant was reported in a tumor, but confirmed maternity, paternity, parental testing, and family-history information are absent.
PS3	Met	Met, strong: L861Q caused transformation, tumors in all mice, IL-3 independence, phosphorylation, and erlotinib-sensitive cell death versus wild-type or empty-vector controls.	PMID:17177598
PS4	Not assessed	Not assessed: one affected patient is reported, but no matched control frequency, odds ratio, relative risk, or confidence interval is available for the PS4 >5.0 requirement.	PMID:15118073
PM1	Met	Met: L861 lies in EGFR's tyrosine-kinase domain and a statistically significant Cancer Hotspots hotspot, with 126 COSMIC observations.	hotspots cosmic PMID:15118073 PMID:17177598
PM2	Met	Met at supporting: the variant was absent from gnomAD v2.1, v4.1, and non-cancer subsets, giving 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive-disease context, pathogenic partner variant, or parental/offspring testing establishes a pathogenic variant in trans.	clinvar
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 different missense substitution at Leu861 was documented as determined pathogenic in the available evidence.	pm5_candidates PMID:15118073 PMID:17177598
PM6	Not assessed	Not assessed: no germline origin or de novo evidence is documented, and parental testing is unavailable.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or familial genotype-phenotype segregation data are reported.
PP2	Not assessed	Not assessed: missense gain-of-function is documented, but no gene-wide rate showing low benign missense variation is available.	gnomad_v2 gnomad_v4 PMID:17177598
PP3	Met	Met at supporting: missense REVEL 0.864 exceeds the PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: no highly specific patient phenotype or family history for a disease with a single genetic etiology is documented.	PMID:15118073
PP5	Not met	Not met: ClinVar has zero expert-panel submissions, and its exact-variant Likely pathogenic assertion is an ordinary laboratory submission without assertion criteria.	clinvar
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, giving 0 observed frequency versus the >=5% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: observed frequency was 0 in gnomAD v2.1, v4.1, and reported non-cancer subsets, below the generic 1% BS1 default.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: population absence does not document a healthy adult carrier, homozygote, or hemizygote required for BS2.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: L861Q showed activating effects and tumor formation rather than evidence of no damaging effect on protein function or splicing.	PMID:17177598
BS4	Not assessed	Not assessed: no affected relatives with negative variant testing or other family non-segregation evidence are documented.
BP1	Not assessed	Not assessed: the evidence does not show that EGFR disease is caused primarily by truncating variants.	oncokb PMID:15118073 PMID:17177598
BP2	Not assessed	Not assessed: no pathogenic partner variant or phase result shows the variant in trans or cis under the BP2 rule.	clinvar
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: missense REVEL 0.864 is above the BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: the case lacks documented evidence of a separate alternate molecular basis for the disease.	PMID:15118073
BP6	Not met	Not met: ClinVar has no expert-panel benign or likely benign assertion for the exact EGFR c.2582T>A variant.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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