Variant classification summary

NM_005228.5:c.2390G>C

EGFR · NP_005219.2:p.(Cys797Ser) · NM_005228.5

GRCh37: chr7:55249092 G>C · GRCh38: chr7:55181399 G>C

Gene: EGFR Transcript: NM_005228.5

Final call

VUS

PS3 moderate PM2 supporting BP5 supporting

Variant details

Gene

EGFR

Transcript

NM_005228.5

Protein

NP_005219.2:p.(Cys797Ser)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Moderate: independent cell-based studies showed C797S resistance to multiple EGFR inhibitors and altered EGFR signaling.

2

PM2 Supporting: the variant is absent from gnomAD v2.1 and v4.1.

3

BP5 Supporting: C797S was reported with pre-existing exon 19 deletion and T790M, an alternate molecular basis for the cancer.

Final determination: Under generic ACMG/AMP 2015 rules, PS3 Moderate plus PM2 Supporting does not reach a pathogenic or likely pathogenic threshold, and BP5 Supporting does not satisfy a benign rule; therefore the call is VUS.

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: EGFR p.Cys797Ser is repeatedly reported, but no previously established pathogenic comparator classification is available for the PS1 requirement.	PMID:25948633 PMID:25964297 PMID:26181354 oncokb spliceai
PS2	Not assessed	Not assessed: confirmed maternity and paternity, relevant disease phenotype, and absence of family history are not documented.
PS3	Met	Met at moderate strength: independent cell-based studies showed C797S resistance to AZD9291, CO-1686, WZ4002, and dacomitinib, with reduced EGFR phosphorylation or altered inhibitor response.	PMID:25939061 PMID:25964297 PMID:25948633 PMID:29410323
PS4	Not assessed	Not assessed: reviewed reports lack an affected-versus-control comparison, OR/RR, and confidence interval required for PS4.	PMID:25939061 PMID:25948633 PMID:29410323 PMID:26181354 PMID:26749488
PM1	Not assessed	Not assessed: C797 lies in EGFR's kinase ATP-binding pocket, but evidence does not establish the required absence of benign variation in that domain or hotspot.	PMID:25964297 PMID:26181354 hotspots
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed AF 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	N/A	Not applicable: no recessive EGFR disorder or affected-proband observation establishes a qualifying in-trans pathogenic variant.	clinvar cosmic PMID:26181354
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: EGFR C797G was functionally studied, but no different C797 missense variant is established as pathogenic for the PM5 requirement.	PMID:26378037 PMID:25964297 PMID:25948633
PM6	Not assessed	Not assessed: an assumed de novo occurrence and the parental-testing status needed for PM6 are not documented.
PP1	Not assessed	Not assessed: no affected relatives, concordant phenotypes, variant results, or informative meioses are documented for co-segregation.
PP2	Not assessed	Not assessed: available EGFR evidence is somatic and variant-specific, without gene-level proof of low benign missense variation and a common missense disease mechanism.
PP3	Not met	Not met: missense REVEL score 0.516 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not met	Not met: reported non-small-cell lung cancer and treatment resistance are not phenotypes highly specific to a single genetic etiology.	PMID:25939061 PMID:26181354 PMID:26749488
PP5	Not met	Not met: ClinVar shows one single-submitter uncertain-significance record and no exact-variant expert-panel pathogenic classification.	clinvar oncokb
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, providing no grpmax FAF at or above the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, so no filtering AF/grpmax FAF reaches the 0.01 BS1 default or exceeds disorder expectations.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult carrying the variant was supplied, and gnomAD absence cannot substitute for a healthy-adult observation.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: variant-specific assays consistently showed drug resistance and reduced inhibitor-mediated EGFR phosphorylation rather than no damaging effect.	PMID:25939061 PMID:25964297 PMID:25948633 PMID:29410323
BS4	Not assessed	Not assessed: no tested affected relatives lacking the variant, or phenocopy evaluation, is documented for non-segregation.
BP1	Not assessed	Not assessed: no gene-level evidence shows that EGFR disease is caused primarily by truncating rather than missense variants.
BP2	Not assessed	Not assessed: reported C797S/T790M cis phase is somatic acquired-resistance evidence, not a germline pathogenic-variant observation.	PMID:26181354 clinvar cosmic
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 score 0.516 is above the BP4 supporting threshold of 0.29.	revel
BP5	Met	Met at supporting strength: C797S was reported with pre-existing exon 19 deletion and T790M that provide an alternate molecular basis for lung cancer.	PMID:25939061 PMID:26181354 PMID:26749488 PMID:25948633
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification is available; the sole record is uncertain significance.	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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