NM_005228.4:c.2317_2318insCCCACCCCA

EGFR · NP_005219.2:p.(His773delinsProHisProAsn) · NM_005228.4

GRCh37: chr7:55249019 C>CCCCACCCCA · GRCh38: chr7:55181326 C>CCCCACCCCA

Gene: EGFR Transcript: NM_005228.4

Final call

VUS

PM2 supporting PM4 moderate

Variant details

Gene

EGFR

Transcript

NM_005228.4

Protein

NP_005219.2:p.(His773delinsProHisProAsn)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005228.4:c.2317_2318insCCCACCCCA (p.His773delinsProHisProAsn) is an in-frame insertion in exon 20 of EGFR, within the tyrosine kinase domain.

This variant is absent from population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_supporting).

The in-frame insertion in a non-repeat functional domain meets PM4 at moderate strength.

No variant-specific functional studies were identified in five reviewed publications; OncoKB classifies the variant as Likely Oncogenic in a somatic context, but this does not independently satisfy germline PS3.

The variant is absent from ClinVar; no expert panel or submitter classification is available.

The variant is not in a statistically significant mutational hotspot per Cancer Hotspots analysis, and in silico splicing predictors (SpliceAI max delta 0.08) do not indicate a splice effect.

Overall, 1 moderate criterion (PM4) and 1 supporting criterion (PM2) are met. This does not reach the threshold for Likely Pathogenic (requires ≥2 moderate + ≥2 supporting, ≥3 moderate, or 1 strong + ≥1 moderate). The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 criteria.

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	This is an in-frame insertion (p.His773delinsProHisProAsn), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus variant). The generic PVS1 framework does not apply.	pvs1_generic_framework
PS1	N/A	PS1 applies to missense variants with a previously established pathogenic variant at the same amino acid position. This is an in-frame insertion/deletion, not a missense change.
PS2	Not assessed	No de novo data available for this variant. De novo occurrence with confirmed maternity and paternity has not been reported.
PS3	Not met	No variant-specific functional studies were identified in the reviewed literature. OncoKB classifies this variant as Likely Oncogenic (gain-of-function) in a somatic cancer context, but this does not independently meet the threshold for germline PS3 functional evidence. Five peer-reviewed publications were reviewed in full text; none mention NM_005228.4:c.2317_2318insCCCACCCCA or its protein equivalents.	oncokb
PS4	Not assessed	No case-control studies comparing variant prevalence in affected individuals versus controls are available. The variant is absent from gnomAD population controls but affected cohort data are lacking.
PS5	Not met	This variant is absent from ClinVar; no reputable source has recently reported it as pathogenic.	clinvar
PM1	Not met	Cancer Hotspots analysis indicates this residue is not a statistically significant mutational hotspot. Although the variant lies within the EGFR tyrosine kinase domain (a critical functional domain), the residue-level hotspot metric is negative.
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, supporting pathogenicity under PM2 (allele frequency <0.1% in population controls).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per adjudication instructions.
PM4	Met	This variant is an in-frame insertion (p.His773delinsProHisProAsn) in exon 20 of EGFR, a non-repeat region encoding the tyrosine kinase domain. In-frame insertions/deletions in non-repeat regions meet PM4 at moderate strength.
PM5	N/A	PM5 applies to novel missense variants at a residue where a different pathogenic missense change has been documented. This is an in-frame insertion/deletion, not a missense variant. The PM5 candidate search confirmed no eligible comparators.	pm5_candidates
PM6	Not assessed	No de novo data (without confirmed maternity and paternity) are available for this variant.
PP1	Not assessed	No cosegregation data in affected family members are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is an in-frame insertion, not a missense variant.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score 0.08). Standard in silico missense predictors (REVEL, BayesDel) are not applicable to in-frame insertions. No multiple lines of computational evidence support a deleterious effect.	spliceai
PP4	Not assessed	No patient phenotype or family history data are available to evaluate disease specificity.
PP5	Not met	This variant is absent from ClinVar; no reputable source has reported it as pathogenic.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No observation of this variant in a healthy adult individual for a fully penetrant disorder has been reported.
BS3	Not met	OncoKB classifies this variant as Likely Oncogenic with a gain-of-function biological effect. Functional evidence does not support a benign interpretation.	oncokb
BS4	Not assessed	No family segregation data are available to evaluate lack of cosegregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. This is an in-frame insertion, not a missense variant.
BP2	Not assessed	No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder has been reported.
BP3	Not met	This is an in-frame insertion in the EGFR tyrosine kinase domain, a well-established functional domain, not a repetitive region without known function. BP3 does not apply.
BP4	Not met	While SpliceAI predicts no splice impact (max delta 0.08), OncoKB classifies the variant as Likely Oncogenic with gain-of-function effect. The totality of evidence does not support multiple lines of computational evidence suggesting no impact.	spliceai oncokb
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6	Not met	This variant is absent from ClinVar; no reputable source has reported it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is an in-frame insertion, not a synonymous variant.

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.