About EGFR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EGFR c.2146A>G, p.(Lys716Glu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_005228.4:c.2146A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Allele frequency is 0% across all population databases, meeting the PM2 threshold for variants absent or present at extremely low frequency (<0.1%) in large population cohorts.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EGFR, a receptor tyrosine kinase, is altered by amplification and/or mutation in lung and brain cancers among others.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV104369001, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 23 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005228.4:c.2146A>G (p.Lys716Glu) is a missense variant in EGFR exon 18, encoding part of the kinase domain ATP-binding pocket. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_supporting).
In silico predictions are indeterminate: REVEL score 0.426 and BayesDel score 0.075 fall between benign and pathogenic thresholds; SpliceAI predicts no splicing impact (max delta 0.00). Neither PP3 nor BP4 is met.
The variant has been reported once in a somatic context in a patient with lung adenocarcinoma enrolled in a study of non-classical EGFR mutations; p.Lys716Glu was classified as a resistant mutation to afatinib (progressive disease, PFS 1.1 months) (PMID:28676220). This observation does not meet PS3 or PS4 thresholds in a germline variant interpretation context.
No experimental functional data, no segregation data, no de novo reports, and no pathogenic ClinVar classifications exist for this variant. ClinVar reports Uncertain significance from two clinical laboratories.
With a single supporting-level criterion (PM2_supporting) and no other criteria met in either the pathogenic or benign direction, this variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination rules.
No criteria match.
Met · 1
PM2 SupportingNM_005228.4:c.2146A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Allele frequency is 0% across all population databases, meeting the PM2 threshold for variants absent or present at extremely low frequency (<0.1%) in large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AC=0).
- Absent from gnomAD v4.1 (AC=0).
- Absent from gnomAD-Canada v1.0 (AC=0).
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No known pathogenic variant at NM_005228.4 nucleotide position c.2146 with a different nucleotide change leading to the same amino acid substitution (p.Lys716Glu) has been identified in ClinVar or the literature. PS1 requires a different nucleotide change at the same codon producing the same missense change with established pathogenicity. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at c.2146 identified.
PS2 No de novo occurrence has been documented for NM_005228.4:c.2146A>G in the available literature or case materials. No germline parent-of-origin or trio sequencing data are available. Details ▾Hide ▴
Evidence considered
- No de novo data available for this variant.
Still missing
- No trio or parent-of-origin data available.
PS3 No experimental functional data (biochemical, cellular, or animal model) exists for p.Lys716Glu. The variant was observed in one patient in PMID:28676220 as a somatic EGFR mutation in lung adenocarcinoma, where it was classified as resistant to afatinib based on clinical outcome (progressive disease, PFS 1.1 months). This constitutes a clinical drug-response observation, not experimental functional evidence. No systematic range characterization (tiling screen, saturation mutagenesis, truncation series) includes this residue. Domain-level inference from exon 18 mutation patterns does not qualify for PS3. Details ▾Hide ▴
Evidence considered
- PMID:28676220 reports K716E as resistant to afatinib in a somatic NSCLC context — clinical observation only
- no experimental functional assay.
Still missing
- No in vitro kinase assay
- no biochemical characterization of p.Lys716Glu
- no systematic range characterization.
Sources
PS4 The variant has been observed in one patient in PMID:28676220 in a somatic NSCLC context and once in COSMIC (COSV104369001). No germline case-control data exist. PS4 requires statistically significant enrichment in affected individuals versus controls, which cannot be established from a single somatic observation. Details ▾Hide ▴
Evidence considered
- PMID:28676220: 1 somatic NSCLC patient with K716E.
- COSMIC: 1 somatic count (COSV104369001).
Still missing
- No germline case-control study data.
- No statistically significant enrichment demonstrated.
Sources
PM1 The variant p.Lys716Glu is located in EGFR exon 18, which encodes part of the ATP-binding pocket within the kinase domain — a critical functional domain. However, residue K716 is not a statistically significant mutational hotspot per cancerhotspots.org, and there is no evidence of pathogenic variant clustering at this specific residue. Domain membership alone, without hotspot-level residue significance, is insufficient for PM1. Details ▾Hide ▴
Evidence considered
- EGFR kinase domain is a critical functional domain
- but K716 is not a statistically significant hotspot residue (cancerhotspots.org: not significant).
Still missing
- No pathogenic variant cluster at K716.
PM6 No de novo germline observation has been documented for this variant. The single observation in PMID:28676220 is a somatic finding in a 59-year-old male with lung adenocarcinoma and does not constitute a de novo germline event with confirmed maternity/paternity. Details ▾Hide ▴
Evidence considered
- PMID:28676220 reports somatic K716E in a lung adenocarcinoma patient — not a germline de novo event.
Still missing
- No trio-based de novo analysis available.
Sources
PP1 No segregation data are available for this variant. No family studies or co-segregation analyses have been reported in the literature. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family-level segregation data.
PP2 HCI prior probability is not available for EGFR (gene not supported by the HCI prior dataset). PP2 requires a gene-specific prior probability of pathogenicity for missense variants, which cannot be assessed without HCI or equivalent data. The variant is a missense change in a disease gene with a low rate of benign missense variation, but without the quantified prior probability, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior not available for EGFR.
Still missing
- No HCI prior or equivalent gene-specific missense constraint metric.
PP3 In silico predictions are indeterminate: REVEL score is 0.426 (below the 0.5 threshold for deleterious prediction), BayesDel score is 0.075 (below typical deleterious thresholds), and SpliceAI predicts no splicing impact (max delta = 0.00). No individual tool or combination of tools provides supporting evidence for a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.426 (indeterminate).
- BayesDel: 0.075 (indeterminate).
- SpliceAI: max delta 0.00 (no splicing impact).
Sources
PP4 No patient phenotype information is available for this variant in a germline context. PP4 requires the patient's phenotype or family history to be highly specific for the disease associated with the gene. The single somatic observation in PMID:28676220 describes a lung adenocarcinoma patient but provides no germline phenotype specificity. Details ▾Hide ▴
Evidence considered
- PMID:28676220: lung adenocarcinoma patient (somatic)
- no germline phenotype specificity reported.
Still missing
- No germline patient phenotype information available.
Sources
PP5 No reputable source has classified this variant as pathogenic. ClinVar reports Uncertain significance from 2 clinical laboratories. The PMIDs associated with the ClinVar submission (28676220, 35274704, 25394175, 26467025) were reviewed; none provides variant-specific evidence for pathogenicity in a germline context. PMID:25394175 is a general cancer genetics referral guideline, not a variant-specific report. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance.
- PMID:25394175: ACMG/NSGC practice guideline
- not variant-specific.
Sources
BA1 The variant is absent from all gnomAD population databases (v2.1, v4.1, Canada). Allele frequency is 0%, far below the BA1 threshold of >1% in any population. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD populations (AF=0%).
Sources
BS1 The variant is absent from all gnomAD population databases. Allele frequency is 0%, far below the BS1 threshold of >0.3% in any population. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD populations (AF=0%).
Sources
BS2 The variant has not been observed in healthy adult controls. It is absent from population databases including gnomAD. No evidence of observation in a healthy individual exists. Details ▾Hide ▴
Evidence considered
- Not observed in any healthy control population.
BS3 No functional studies demonstrating a benign effect for p.Lys716Glu exist. The single clinical observation in PMID:28676220 reports drug resistance to afatinib in a somatic NSCLC context, which is a clinical outcome observation and does not constitute experimental functional evidence for or against pathogenicity. Details ▾Hide ▴
Evidence considered
- PMID:28676220: clinical drug resistance observation only
- not experimental functional data showing normal protein function.
Still missing
- No functional studies demonstrating normal protein activity
- expression
- or localization.
Sources
BS4 No segregation data are available for this variant. BS4 requires lack of segregation with disease in affected family members, which cannot be assessed without family-level data. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family-level segregation data.
BP1 NM_005228.4:c.2146A>G is a missense variant, not a truncating variant. BP1 applies when a truncating variant is observed in a gene where the primary disease mechanism is missense (gain-of-function). This criterion is for truncating variants in genes with alternative mechanisms; a missense variant does not qualify for BP1. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP1 applies only to truncating variants in genes where LOF is not the disease mechanism.
BP2 No co-occurrence data with a known pathogenic variant in EGFR are available. BP2 requires observation in trans (for recessive disorders) or in cis (for dominant disorders) with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No co-occurrence data with a pathogenic EGFR variant.
Still missing
- No phase-known co-occurrence data available.
BP4 In silico predictions are indeterminate: REVEL score 0.426 and BayesDel score 0.075 fall between benign and pathogenic thresholds. SpliceAI predicts no splicing impact (max delta = 0.00). No tool provides strong evidence for a benign effect. BP4 requires multiple lines of computational evidence to suggest no impact on the gene or gene product, which is not established from these indeterminate scores. Details ▾Hide ▴
Evidence considered
- REVEL: 0.426 (indeterminate
- not clearly benign).
- BayesDel: 0.075 (indeterminate
- near-zero).
- SpliceAI: max delta 0.00 (no splicing impact).
Sources
BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease. BP5 requires that the variant is observed in an individual with a different molecular cause for the phenotype, which is not documented. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause for disease identified in patients with this variant.
Still missing
- No data on alternate molecular diagnoses in carriers.
BP6 No reputable source has classified this variant as benign. ClinVar reports Uncertain significance. BP6 requires a reputable source to classify the variant as benign or likely benign with the evidence available for independent review. Details ▾Hide ▴
BP7 NM_005228.4:c.2146A>G is a missense variant (p.Lys716Glu), not a synonymous variant. BP7 applies only to synonymous variants where splicing algorithms predict no impact on the splice consensus sequence. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
PS5 ClinVar classifies this variant as Uncertain significance (2 clinical laboratories, variation ID 2681884). No reputable source has classified it as pathogenic. PS5 requires a reputable source to have reported the variant as pathogenic without the primary evidence being available for independent review. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- criteria provided
- single submitter (2 labs).
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_005228.4:c.2146A>G is a missense variant (p.Lys716Glu). PVS1 is reserved for null variants (nonsense, frameshift, or canonical ±1,2 splice site) where loss of function is the established disease mechanism. This substitution does not fall into any null-variant bucket under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- no null-variant classification under PMC6185798.
Sources
PM5 N/ANo pathogenic comparator variants at the same amino acid residue (p.Lys716) were identified in ClinVar. The PM5 candidate search returned zero eligible comparators, so same-residue pathogenic comparator assessment cannot be performed. Details ▾Hide ▴
Evidence considered
- No pathogenic variant at residue K716 found in ClinVar.
Identifiers
- Gene
- EGFR
- Transcript
- NM_005228.4
- Coding (HGVS c.)
- NM_005228.4:c.2146A>G
- Protein (HGVS p.)
- NP_005219.2:p.(Lys716Glu)
- GRCh38
- chr7:55174005 A>G
- GRCh37
- chr7:55241698 A>G
- ClinVar
- 2681884
- COSMIC
- COSV104369001
Gene diagram
Every interpreted variant in EGFR, mapped onto the exon structure of NM_005228.4. Select a row to find it on the plot.
EGFRNM_005228.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in EGFR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.426
- BayesDel
- 0.075
How the predictions were used
PP3 In silico predictions are indeterminate: REVEL score is 0.426 (below the 0.5 threshold for deleterious prediction), BayesDel score is 0.075 (below typical deleterious thresholds), and SpliceAI predicts no splicing impact (max delta = 0.00). No individual tool or combination of tools provides supporting evidence for a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.426 (indeterminate).
- BayesDel: 0.075 (indeterminate).
- SpliceAI: max delta 0.00 (no splicing impact).
Sources
BP4 In silico predictions are indeterminate: REVEL score 0.426 and BayesDel score 0.075 fall between benign and pathogenic thresholds. SpliceAI predicts no splicing impact (max delta = 0.00). No tool provides strong evidence for a benign effect. BP4 requires multiple lines of computational evidence to suggest no impact on the gene or gene product, which is not established from these indeterminate scores. Details ▾Hide ▴
Evidence considered
- REVEL: 0.426 (indeterminate
- not clearly benign).
- BayesDel: 0.075 (indeterminate
- near-zero).
- SpliceAI: max delta 0.00 (no splicing impact).
Sources
BP7 NM_005228.4:c.2146A>G is a missense variant (p.Lys716Glu), not a synonymous variant. BP7 applies only to synonymous variants where splicing algorithms predict no impact on the splice consensus sequence. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.426. BayesDel score = 0.0749666.
4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016Describes a rules-based scoring system for DNA variant pathogenicity classification in Mendelian disorders, analyzing over 16,500 assessments on 11,894 variants from 338 genes. K716E or EGFR:c.2146A>G is not mentioned.Does not name this variant
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PMID 35274704 ↗Tyrosine Kinase Inhibitor Activity in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Retrospective International Cohort Study (UpSwinG).Popat S et al. · 2022The UpSwinG study evaluates EGFR TKI activity in NSCLC patients harboring uncommon EGFR mutations, including major uncommon mutations (G719X, L861Q, S768I) and compound mutations. K716E is not listed among the uncommon mutations analyzed in this cohort.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline providing referral criteria for cancer predisposition assessment. Lists hereditary cancer syndromes and referral indications. Does not mention EGFR mutation testing or any specific EGFR variant.Does not name this variant
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PMID 28676220 ↗Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations.Shen YC et al. · 2017K716E reported in a 59-year-old male with advanced-stage lung adenocarcinoma and a non-classical EGFR mutation. The patient received afatinib and had progressive disease with PFS of 1.1 months. K716E was classified as a resistant mutation along with V717G, I715V, and others.Names this variant
Quoted passage
K716E 59 Male 1 PD 1.1
Table 2 (mutation list), Table 4 (clinical outcomes), Results paragraph discussing rarely reported EGFR mutations
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2681884/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-55241698-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-55174005-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-55174005-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005228.4%3Ac.2146…
- OncoKB ↗www.oncokb.org/gene/EGFR/K716E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120762780
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 2681884)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.426. BayesDel score = 0.0749666.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EGFR, a receptor tyrosine kinase, is altered by amplification and/or mutation in lung and brain cancers among others.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104369001, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.