About NFE2L2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NFE2L2 c.100C>G, p.(Arg34Gly)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
The variant is located at codon 34 (Arg34) within the Neh2 domain (residues 16–89), the KEAP1-binding degron that is a critical and well-established functional domain. Arg34 is a statistically significant cancer hotspot residue (Cancer Hotspots), and other missense alterations at this codon (R34Q, R34P) are recurrently observed in NSCLC and other cancers. The variant is absent from gnomAD population databases, indicating no benign variation at this position.
PM2Supporting
PM2 · supporting
NM_006164.4:c.100C>G is absent from gnomAD v2.1 and v4.1 population databases (allele frequency <0.1%), meeting the PM2 threshold for a rare variant absent from population controls.
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: PM1 moderate, PM2 supporting; combination = 1 moderate + 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.
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
Not recorded
A ClinVar laboratory submission summary was not recorded.
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
42 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV67960061, n = 42 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: 2 met · 6 not met · 14 not assessed · 7 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.100C>G (p.Arg34Gly) is a missense variant in exon 2 of NFE2L2. It is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
The variant is located at codon 34 within the Neh2 domain (residues 16–89), the KEAP1-binding degron that is a critical and well-established functional domain. Arg34 is a statistically significant cancer hotspot residue, and other missense alterations at this codon (R34Q, R34P) are recurrently observed in NSCLC and other cancers with no benign variation at this codon (PM1).
The variant has been reported in COSMIC (COSV67960061, n=42) as a somatic mutation. OncoKB classifies it as Likely Oncogenic (somatic context). These somatic observations do not directly inform germline pathogenicity under ACMG/AMP.
In silico predictions are equivocal: REVEL score 0.543 (borderline), BayesDel score 0.170 (low), and SpliceAI max delta 0.00. These do not meet the threshold for PP3 or BP4.
No functional studies, case-control data, de novo observations, segregation data, or authoritative germline classifications are available for this variant. The majority of criteria cannot be assessed.
Applying the generic ACMG/AMP 2015 combination rules: PM1 (moderate) + PM2_Supporting (supporting) = 1 moderate + 1 supporting. This is insufficient for a Likely Pathogenic classification (requires 2 moderate, or 1 strong + 1 moderate, or 1 strong + ≥2 supporting). No benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM1 ModerateThe variant is located at codon 34 (Arg34) within the Neh2 domain (residues 16–89), the KEAP1-binding degron that is a critical and well-established functional domain. Arg34 is a statistically significant cancer hotspot residue (Cancer Hotspots), and other missense alterations at this codon (R34Q, R34P) are recurrently observed in NSCLC and other cancers. The variant is absent from gnomAD population databases, indicating no benign variation at this position. Details ▾Hide ▴
Evidence considered
- Located at Arg34 in the Neh2 KEAP1-binding domain (residues 16–89).
- Cancer Hotspots identifies codon 34 as a statistically significant hotspot.
- Other missense variants at codon 34 (R34Q/c.101G>A
- R34P/c.101G>C) are reported as somatic mutations in NSCLC and other cancers in PMID:23936606.
- Variant is absent from gnomAD v2.1 and v4.1
- indicating no benign variation at this codon.
Sources
PM2 SupportingNM_006164.4:c.100C>G is absent from gnomAD v2.1 and v4.1 population databases (allele frequency <0.1%), meeting the PM2 threshold for a rare variant absent from population controls. Details ▾Hide ▴
Not met · 6 · evaluated, threshold not reached
PP3 In silico predictions do not provide consistent support for a deleterious effect. REVEL score is 0.543 (borderline; just above the 0.5 threshold), BayesDel score is 0.170 (below typical damaging thresholds of ~0.27), and SpliceAI predicts no splicing impact (max delta score 0.00). The computational evidence is insufficiently robust to meet PP3. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.543 (borderline).
- BayesDel score: 0.170 (low).
- SpliceAI max delta: 0.00 (no predicted impact).
Sources
PP5 No reputable source has reported NM_006164.4:c.100C>G as pathogenic. ClinVar Variation ID 3258027 has no classification. OncoKB classifies the variant as Likely Oncogenic in a somatic context, which does not constitute a germline pathogenicity assertion. Details ▾Hide ▴
BA1 The variant is absent from gnomAD v2.1 and v4.1 population databases. Allele frequency is well below the BA1 threshold of >1%. Details ▾Hide ▴
BS1 The variant is absent from gnomAD v2.1 and v4.1. Allele frequency is well below the BS1 threshold of >0.3%. Details ▾Hide ▴
BP4 In silico predictions do not provide consistent evidence for a benign effect. REVEL score is 0.543 (above the neutral range), and BayesDel score is 0.170. The computational evidence does not meet the threshold for multiple lines of evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.543 (not clearly benign).
- BayesDel score: 0.170 (low but not definitively benign).
- SpliceAI max delta: 0.00.
Sources
BP6 No reputable source has reported NM_006164.4:c.100C>G as benign. ClinVar Variation ID 3258027 has no classification. Details ▾Hide ▴
Not assessed · 14 · no assessment recorded
PS1 No other pathogenic missense variant at codon 34 (Arg34) with a different amino acid change was identified for comparison. No evidence available to apply PS1. Details ▾Hide ▴
Still missing
- No established pathogenic comparator variant at Arg34 available.
PS2 No de novo observation of NM_006164.4:c.100C>G with confirmed maternity/paternity has been reported in the literature or ClinVar. Details ▾Hide ▴
Still missing
- No de novo reports identified for this variant.
PS3 No well-established functional assay data are available for NM_006164.4:c.100C>G (p.Arg34Gly) demonstrating a deleterious effect in a germline disease context. OncoKB curation suggests likely gain-of-function in somatic cancer but this does not constitute a validated germline functional assay. Details ▾Hide ▴
Evidence considered
- OncoKB classifies as Likely Oncogenic (somatic context)
- no germline functional assay data available.
Still missing
- No direct functional studies of p.Arg34Gly in KEAP1 binding
- NRF2 transcriptional activity
- or germline-relevant cellular assays.
Sources
PS4 No case-control studies or enrichment data are available comparing the prevalence of NM_006164.4:c.100C>G in affected individuals versus controls. The variant has been observed in COSMIC (42 somatic occurrences) but these are somatic observations, not germline case-control data. Details ▾Hide ▴
Evidence considered
- COSMIC reports 42 somatic occurrences (COSV67960061)
- no germline case-control data available.
Still missing
- No germline case-control studies or enrichment analysis for this variant.
PM6 No de novo observation of NM_006164.4:c.100C>G without confirmation of maternity/paternity has been reported. Details ▾Hide ▴
Still missing
- No de novo reports identified.
PP1 No cosegregation data are available for NM_006164.4:c.100C>G in families with NFE2L2-related disease. Details ▾Hide ▴
Still missing
- No family segregation studies reported.
PP2 PP2 requires a low rate of benign missense variation in the gene and missense variants as a common disease mechanism. HCI prior data are unavailable for NFE2L2. Without a gene-specific missense constraint metric, PP2 cannot be reliably applied under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- HCI prior not available for NFE2L2
- gene-level missense constraint cannot be assessed.
Still missing
- No gene-specific missense constraint metric (e.g.
- HCI prior) available for NFE2L2.
PP4 No well-defined germline disease phenotype with high specificity is associated with NFE2L2 variants. The phenotype or family history cannot be evaluated for PP4. Details ▾Hide ▴
Still missing
- No established germline NFE2L2 disease phenotype with defined specificity.
BS2 No observation of this variant in healthy adults in the context of a fully penetrant NFE2L2-related disorder has been documented. The absence from gnomAD is noted but BS2 specifically requires observation in a well-phenotyped healthy cohort for a disorder with full penetrance. Details ▾Hide ▴
Still missing
- No well-phenotyped healthy cohort data for a fully penetrant NFE2L2 disorder.
BS3 No well-established functional studies demonstrate that NM_006164.4:c.100C>G has no damaging effect on protein function or splicing. The available in silico data do not constitute functional assay evidence for BS3. Details ▾Hide ▴
Still missing
- No functional assay data demonstrating normal protein function for this variant.
BS4 No data are available on non-segregation of NM_006164.4:c.100C>G with disease in affected families. Details ▾Hide ▴
Still missing
- No segregation data available.
BP1 BP1 applies when a missense variant is found in a gene where primarily truncating variants cause disease. NFE2L2 somatic mutations are predominantly missense gain-of-function alterations in the KEAP1-binding domain. Without a clearly defined germline disease mechanism where truncation is the primary cause, BP1 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
- NFE2L2 somatic disease mechanism is primarily missense gain-of-function
- germline disease mechanism not well characterized.
Still missing
- No clearly defined germline NFE2L2 disease mechanism establishing truncation as the primary pathogenic variant type.
BP5 No case has been reported in which NM_006164.4:c.100C>G was found in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No cases with alternate molecular basis reported.
PS5 No reputable source has recently reported NM_006164.4:c.100C>G as definitively pathogenic with evidence unavailable for independent evaluation. ClinVar Variation ID 3258027 has no classification from any submitter. Details ▾Hide ▴
Evidence considered
- ClinVar ID 3258027: no classification available
- no submissions with criteria.
Still missing
- No authoritative source reports this variant as pathogenic.
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006164.4:c.100C>G is a missense variant (p.Arg34Gly). It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable for missense changes. Details ▾Hide ▴
PM3 N/APM3 applies to variants detected in trans with a pathogenic variant in a recessive disorder. NFE2L2 is not established as causing an autosomal recessive disorder. Details ▾Hide ▴
Evidence considered
- No established autosomal recessive NFE2L2 disorder.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants altering protein length. This variant is a single-nucleotide missense substitution, not a protein-length-altering change. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a protein-length-altering variant.
PM5 N/ANo established pathogenic missense variant at the same residue (Arg34) with a different amino acid change was identified for PM5 comparator analysis. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: no eligible comparator candidates
- PM5 mode unknown.
Sources
pm5_candidates
BP2 N/ABP2 requires observation of the variant in trans with a pathogenic variant in a fully penetrant autosomal recessive disorder. NFE2L2 is not established as causing a recessive disease. Details ▾Hide ▴
Evidence considered
- NFE2L2 is not known to cause an autosomal recessive disorder.
BP3 N/ABP3 applies to in-frame indels in repetitive regions without a known function. This variant is a single-nucleotide missense substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_006164.4:c.100C>G is a missense variant (p.Arg34Gly), not a synonymous change. Details ▾Hide ▴
Evidence considered
- This is a missense variant
- not a synonymous variant.
Identifiers
- Gene
- NFE2L2
- Transcript
- NM_006164.4
- Coding (HGVS c.)
- NM_006164.4:c.100C>G
- Protein (HGVS p.)
- NP_006155.2:p.(Arg34Gly)
- GRCh38
- chr2:177234217 G>C
- GRCh37
- chr2:178098945 G>C
- ClinVar
- 3258027
- COSMIC
- COSV67960061
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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.543
- BayesDel
- 0.170
How the predictions were used
PP3 In silico predictions do not provide consistent support for a deleterious effect. REVEL score is 0.543 (borderline; just above the 0.5 threshold), BayesDel score is 0.170 (below typical damaging thresholds of ~0.27), and SpliceAI predicts no splicing impact (max delta score 0.00). The computational evidence is insufficiently robust to meet PP3. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.543 (borderline).
- BayesDel score: 0.170 (low).
- SpliceAI max delta: 0.00 (no predicted impact).
Sources
BP4 In silico predictions do not provide consistent evidence for a benign effect. REVEL score is 0.543 (above the neutral range), and BayesDel score is 0.170. The computational evidence does not meet the threshold for multiple lines of evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.543 (not clearly benign).
- BayesDel score: 0.170 (low but not definitively benign).
- SpliceAI max delta: 0.00.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_006164.4:c.100C>G is a missense variant (p.Arg34Gly), not a synonymous change. Details ▾Hide ▴
Evidence considered
- This is a missense variant
- not a synonymous variant.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.543. BayesDel score = 0.170416.
7 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
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PMID 30150714 ↗A catalogue of somatic NRF2 gain-of-function mutations in cancer.Kerins MJ et al. · 2018No paper-specific finding is recorded.
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PMID 21897267 ↗Association of keap1 and nrf2 genetic mutations and polymorphisms with endometrioid endometrial adenocarcinoma survival.No paper-specific finding is recorded.
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PMID 23936606 ↗Genomic structure and variation of nuclear factor (erythroid-derived 2)-like 2.Cho HY · 2013No paper-specific finding is recorded.
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PMID 35101336 ↗Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).Horak P et al. · 2022No paper-specific finding is recorded.
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PMID 22918138 ↗Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.Schrijver I et al. · 2012No paper-specific finding is recorded.
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PMID 34131312 ↗Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).Shao L et al. · 2021No paper-specific finding is recorded.
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PMID 23619274 ↗American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.Cooley LD et al. · 2013No 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
Captured ClinVar source record
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/3258027/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-178098945-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-177234217-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006164.4%3Ac.100C…
- OncoKB ↗www.oncokb.org/gene/NFE2L2/R34G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=150794997
- 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.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 3258027)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.543. BayesDel score = 0.170416.
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; COSV67960061, n = 42 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.