About NFE2L2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NFE2L2 c.101G>A, p.(Arg34Gln)
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: 3
Benign evidence criteria: 1
Pathogenic criteria applied · 3
PS3Supporting
PS3 · supporting
Functional studies in HEK293T cells demonstrate that NRF2-R34Q partially escapes KEAP1-mediated repression (luciferase activity retained at ~60% vs <10% for wild-type upon KEAP1 co-expression). Cycloheximide chase assays show extended protein half-life (31-49 min vs 15 min wild-type), and ubiquitylation is reduced. These findings support a gain-of-function effect consistent with the known NFE2L2 oncogenic mechanism.
PM1Moderate
PM1 · moderate
Arg34 is located in the Neh2 domain (residues 1-98), the KEAP1-binding domain critical for NRF2 regulation. Arg34 is the most frequently mutated NRF2 residue across cancer types (14.2% of all NRF2 mutations in TCGA, per PMID:30150714) and falls within a statistically significant mutational hotspot.
PM2Moderate
PM2 · moderate
NM_006164.4:c.101G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes+genomes), and gnomAD-Canada v1.0 (HostSeq genomes). Population allele frequency = 0.00, which is well below the <0.1% threshold for PM2 in non-VCEP ACMG/AMP.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple in silico prediction tools do not predict a deleterious effect. REVEL score is 0.412 (below the 0.5 pathogenic threshold), BayesDel score is 0.146 (low), and SpliceAI maximum delta score is 0.00 (no predicted splice impact). The concordance of benign predictions across multiple algorithm types supports BP4 at supporting level.
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: PS3 supporting, PM1 moderate, PM2 moderate, BP4 supporting benign; combination = 2 moderate + 1 supporting + 1 supporting benign, 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.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
46 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV67960161, n = 46 times).
Cancer Hotspots
This variant lies 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.
29 criteria with recorded statuses: 4 met · 17 not met · 3 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006164.4:c.101G>A (p.Arg34Gln) in NFE2L2 is a missense variant absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).
The variant is located at Arg34 in the Neh2 domain, the KEAP1-binding domain critical for NRF2 regulation. Arg34 is the most frequently mutated NRF2 residue across cancer types and lies within a statistically significant mutational hotspot.
Functional studies in HEK293T cells demonstrate that NRF2-R34Q partially escapes KEAP1-mediated repression (luciferase activity retained at ~60% vs <10% for wild-type), has extended protein half-life, and shows reduced ubiquitylation, consistent with a gain-of-function effect.
Multiple in silico prediction tools do not predict a deleterious effect: REVEL score 0.412, BayesDel score 0.146, and SpliceAI maximum delta score 0.00.
This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (GeneDx, Labcorp). No de novo observations, cosegregation data, or case-control studies are available.
Applying generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile includes two moderate pathogenic criteria (PM1, PM2), one supporting pathogenic criterion (PS3), and one supporting benign criterion (BP4), resulting in an overall classification of Uncertain significance.
No criteria match.
Met · 4
PS3 SupportingFunctional studies in HEK293T cells demonstrate that NRF2-R34Q partially escapes KEAP1-mediated repression (luciferase activity retained at ~60% vs <10% for wild-type upon KEAP1 co-expression). Cycloheximide chase assays show extended protein half-life (31-49 min vs 15 min wild-type), and ubiquitylation is reduced. These findings support a gain-of-function effect consistent with the known NFE2L2 oncogenic mechanism. Details ▾Hide ▴
Evidence considered
- Luciferase reporter assay: KEAP1 co-expression reduced NRF2-R34Q activity to ~60% vs <10% for WT. Cycloheximide chase: R34Q half-life 31-49 min vs WT 15 min. Reduced ubiquitylation confirmed. All data from a single comprehensive study (Kerins & Ooi 2018).
Still missing
- Single study from one laboratory
- independent replication lacking. Functional evidence derived from somatic cancer context (HEK293T cells)
- no germline-specific functional validation available.
Sources
PMID:30150714 ↗30150714
PM1 ModerateArg34 is located in the Neh2 domain (residues 1-98), the KEAP1-binding domain critical for NRF2 regulation. Arg34 is the most frequently mutated NRF2 residue across cancer types (14.2% of all NRF2 mutations in TCGA, per PMID:30150714) and falls within a statistically significant mutational hotspot. Details ▾Hide ▴
Evidence considered
- Neh2 domain is a critical functional domain for KEAP1 binding. Arg34 is the most frequently mutated NRF2 residue (14.2% of NRF2 mutations
- p<0.05). Cancer Hotspots confirms residue-level statistical significance.
Still missing
- Hotspot evidence is derived from somatic cancer datasets
- germline hotspot data are unavailable.
Sources
PMID:30150714 ↗30150714
PM2 ModerateNM_006164.4:c.101G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes+genomes), and gnomAD-Canada v1.0 (HostSeq genomes). Population allele frequency = 0.00, which is well below the <0.1% threshold for PM2 in non-VCEP ACMG/AMP. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF=null)
- gnomAD v4.1 (AF=null)
- and gnomAD-Canada v1.0 (AF=0.0). No homozygotes observed.
Sources
BP4 SupportingMultiple in silico prediction tools do not predict a deleterious effect. REVEL score is 0.412 (below the 0.5 pathogenic threshold), BayesDel score is 0.146 (low), and SpliceAI maximum delta score is 0.00 (no predicted splice impact). The concordance of benign predictions across multiple algorithm types supports BP4 at supporting level. Details ▾Hide ▴
Evidence considered
- REVEL=0.412 (benign range)
- BayesDel=0.145684 (low impact)
- SpliceAI max delta=0.00 (no splice effect). Three independent algorithm classes concur on benign prediction.
Sources
Not met · 17 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 34 encoding the same amino acid (Arg34Gln) has been established as pathogenic. The only confirmed Arg34Gln change is c.101G>A; other codon 34 changes (c.100C>G p.Arg34Gly, c.101G>C p.Arg34Pro, c.101G>T p.Arg34Leu) have not been classified as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- All four possible R34 mutations (R34G
- R34P
- R34L
- R34Q) are documented in somatic cancer contexts but none are established as germline pathogenic variants with a different nucleotide change from c.101G>A.
Sources
PS2 No confirmed de novo observation of NM_006164.4:c.101G>A has been reported in any published family or cohort. NFE2L2 germline de novo events have not been documented. Details ▾Hide ▴
Evidence considered
- Exploratory literature and database search found no de novo observations for this variant.
Still missing
- No de novo reports identified in literature
- ClinVar
- or Decipher.
PS4 No case-control study has compared the prevalence of NM_006164.4:c.101G>A in affected individuals versus controls. The variant is recurrent in somatic cancers (COSMIC, n=46) but germline case enrichment has not been demonstrated. Details ▾Hide ▴
Evidence considered
- COSMIC reports 46 somatic occurrences (COSV67960161). gnomAD shows absence in population controls. No published case-control or cohort study with odds ratio calculation exists.
Still missing
- Absence of controlled prevalence data comparing affected vs. general population.
Sources
PM5 No pathogenic missense variant at Arg34 with a different amino acid change has been established through ClinVar or the literature. While other R34 mutations (R34G, R34P, R34L) are documented in somatic cancer datasets, none are classified as pathogenic in a germline context. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting found zero eligible comparators. R34G
- R34P
- and R34L are reported in PMID:30150714 but lack established germline pathogenicity.
Still missing
- No same-residue comparator variant with established germline pathogenicity.
Sources
PP1 No cosegregation data are available for NM_006164.4:c.101G>A. No family studies with NFE2L2 germline variants have been published. Details ▾Hide ▴
Evidence considered
- Literature search found no family-based segregation studies for NFE2L2 germline variants.
Still missing
- No family cosegregation data available.
PP2 NFE2L2 is not established as a germline disease gene with a low rate of benign missense variation where missense variants are a common disease mechanism. The HCI prior score is unavailable for NFE2L2. The known disease mechanism is somatic gain-of-function in cancer, not germline Mendelian disease. Details ▾Hide ▴
Evidence considered
- HCI prior not found. NFE2L2 lacks established germline missense constraint metrics. Disease mechanism is somatic gain-of-function.
Still missing
- No germline missense constraint data available for NFE2L2.
PP3 Multiple in silico prediction tools do not support a deleterious effect. REVEL score is 0.412 (below 0.5 threshold), BayesDel score is 0.146 (low), and SpliceAI maximum delta score is 0.00 (no predicted splice impact). These scores collectively argue against computational evidence of pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL=0.412 (<0.5)
- BayesDel=0.145684 (low)
- SpliceAI max delta=0.00. No in silico tool predicts a damaging effect.
Sources
PP4 No specific phenotype or family history data are available for individuals carrying this variant. ClinVar submissions report 'Not Provided' or unspecified conditions, and no detailed clinical phenotypes have been published. Details ▾Hide ▴
Evidence considered
- ClinVar clinical laboratories report non-specific or absent phenotype information. No published clinical descriptions of carriers.
Still missing
- No detailed phenotype data available for variant carriers.
Sources
PP5 No reputable source has classified NM_006164.4:c.101G>A as pathogenic. ClinVar reports Uncertain significance from two clinical laboratories (GeneDx, Labcorp). The ClinVar-cited PMID (28492532) is a methods paper on classification criteria and does not discuss this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (2 submitters). PMID:28492532 (Sherloc) is a classification criteria refinement paper
- does not mention this variant.
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Population allele frequency is 0.00, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.00 in all population databases
- does not approach the 1% BA1 threshold.
Sources
BS1 The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency is 0.00, which is below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.00
- does not meet the >0.3% BS1 threshold.
Sources
BS2 The variant has not been observed in healthy adults. It is absent from gnomAD, which precludes observation in presumed healthy population controls. No published reports document this variant in unaffected individuals with full penetrance expected. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD. No published observation in healthy adults.
Sources
BS3 Well-validated functional studies in PMID:30150714 demonstrate that NRF2-R34Q has a gain-of-function effect (partial escape from KEAP1-mediated repression, extended protein half-life, reduced ubiquitylation), consistent with the known oncogenic mechanism of NFE2L2. This is evidence of a damaging effect, not evidence of no damaging effect as required for BS3. Details ▾Hide ▴
Evidence considered
- NRF2-R34Q retains ~60% luciferase activity under KEAP1 co-expression (vs <10% WT). Extended half-life (31-49 min vs 15 min WT). Reduced ubiquitylation. These findings demonstrate gain-of-function
- not absence of functional impact.
Sources
PMID:30150714 ↗30150714
BS4 No segregation data are available to assess whether this variant segregates with disease in families. No studies have examined cosegregation of NFE2L2 variants with a specific phenotype. Details ▾Hide ▴
Evidence considered
- No family segregation studies available.
Still missing
- Complete absence of segregation data.
BP1 BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. For NFE2L2, the established disease mechanism in cancer is gain-of-function through missense mutations in the Neh2 domain that disrupt KEAP1 binding, not loss-of-function through truncation. Details ▾Hide ▴
Evidence considered
- NFE2L2 disease mechanism is gain-of-function missense
- primarily in the DLG/ETGE motifs and surrounding Neh2 domain. Truncating variants are not the primary mechanism.
Sources
PMID:30150714 ↗30150714
BP2 No observation of NM_006164.4:c.101G>A in trans with a known pathogenic NFE2L2 variant has been reported. Given that NFE2L2-associated phenotypes follow a dominant gain-of-function mechanism, BP2 is unlikely to be applicable. Details ▾Hide ▴
Evidence considered
- No trans observations with pathogenic NFE2L2 variants in ClinVar or literature. Dominant gain-of-function mechanism makes BP2 unlikely.
BP6 No reputable source has classified NM_006164.4:c.101G>A as benign. ClinVar reports Uncertain significance from two clinical laboratories. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (2 submitters). No benign classification from any source.
Sources
Not assessed · 3 · no assessment recorded
PM6 No de novo paternity-confirmed cases of NM_006164.4:c.101G>A have been reported. NFE2L2 germline de novo events are not documented in the literature or ClinVar. Details ▾Hide ▴
Still missing
- No de novo observations with confirmed paternity in any database or publication.
BP5 Insufficient data to determine whether affected individuals carrying this variant have an alternative molecular explanation for their phenotype. Clinical phenotype data are not available. Details ▾Hide ▴
Still missing
- No phenotype or alternate molecular diagnosis data available for variant carriers.
PS5 Insufficient data to determine whether affected individuals with this variant have an alternative molecular cause for their phenotype. No clinical phenotype data are available for the reported ClinVar cases. Details ▾Hide ▴
Still missing
- No phenotype or alternate molecular cause data available for individuals carrying this variant.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006164.4:c.101G>A is a missense variant (p.Arg34Gln). PVS1 applies only to null variants (nonsense, frameshift, canonical splice ±1,2); this variant falls into the 'other' bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- does not meet null-variant criteria for PVS1 application.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ANFE2L2-associated phenotypes follow a dominant gain-of-function mechanism; biallelic observations are not expected. No homozygous or compound heterozygous reports exist, nor are they applicable to this gene. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANM_006164.4:c.101G>A is a single-nucleotide missense substitution, not a non-frameshift deletion/insertion or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ANM_006164.4:c.101G>A is a single-nucleotide missense substitution, not an in-frame insertion/deletion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_006164.4:c.101G>A is a missense variant (p.Arg34Gln), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NFE2L2
- Transcript
- NM_006164.4
- Coding (HGVS c.)
- NM_006164.4:c.101G>A
- Protein (HGVS p.)
- NP_006155.2:p.(Arg34Gln)
- GRCh38
- chr2:177234216 C>T
- GRCh37
- chr2:178098944 C>T
- ClinVar
- 3360940
- COSMIC
- COSV67960161
Gene diagram
Every interpreted variant in NFE2L2, mapped onto the exon structure of NM_006164.4. Select a row to find it on the plot.
NFE2L2NM_006164.4
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 NFE2L2
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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
- 0.412
- BayesDel
- 0.146
How the predictions were used
BP4 SupportingMultiple in silico prediction tools do not predict a deleterious effect. REVEL score is 0.412 (below the 0.5 pathogenic threshold), BayesDel score is 0.146 (low), and SpliceAI maximum delta score is 0.00 (no predicted splice impact). The concordance of benign predictions across multiple algorithm types supports BP4 at supporting level. Details ▾Hide ▴
Evidence considered
- REVEL=0.412 (benign range)
- BayesDel=0.145684 (low impact)
- SpliceAI max delta=0.00 (no splice effect). Three independent algorithm classes concur on benign prediction.
Sources
PP3 Multiple in silico prediction tools do not support a deleterious effect. REVEL score is 0.412 (below 0.5 threshold), BayesDel score is 0.146 (low), and SpliceAI maximum delta score is 0.00 (no predicted splice impact). These scores collectively argue against computational evidence of pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL=0.412 (<0.5)
- BayesDel=0.145684 (low)
- SpliceAI max delta=0.00. No in silico tool predicts a damaging effect.
Sources
BP7 N/ANM_006164.4:c.101G>A is a missense variant (p.Arg34Gln), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.412. BayesDel score = 0.145684.
3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 20421815 ↗NFE2L2 gene mutation in male Japanese squamous cell carcinoma of the lung.No paper-specific finding is recorded.
-
PMID 30150714 ↗A catalogue of somatic NRF2 gain-of-function mutations in cancer.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
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/3360940/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-178098944-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-177234216-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-177234216-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006164.4%3Ac.101G…
- OncoKB ↗www.oncokb.org/gene/NFE2L2/R34Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=150793793
- 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 = 3360940)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.412. BayesDel score = 0.145684.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV67960161, n = 46 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.