NM_006164.4:c.100C>G

NFE2L2 · NP_006155.2:p.(Arg34Gly) · NM_006164.4

GRCh37: chr2:178098945 G>C · GRCh38: chr2:177234217 G>C

Gene: NFE2L2 Transcript: NM_006164.4

Final call

VUS

PM1 moderate PM2 supporting

Variant details

Gene

NFE2L2

Transcript

NM_006164.4

Protein

NP_006155.2:p.(Arg34Gly)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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	NM_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.	pvs1_generic_framework
PS1	Not assessed	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.
PS2	Not assessed	No de novo observation of NM_006164.4:c.100C>G with confirmed maternity/paternity has been reported in the literature or ClinVar.
PS3	Not assessed	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.	oncokb
PS4	Not assessed	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.
PS5	Not assessed	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.	clinvar
PM1	Met	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.	gnomad_v2 gnomad_v4 PMID:23936606
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	No established pathogenic missense variant at the same residue (Arg34) with a different amino acid change was identified for PM5 comparator analysis.	pm5_candidates
PM6	Not assessed	No de novo observation of NM_006164.4:c.100C>G without confirmation of maternity/paternity has been reported.
PP1	Not assessed	No cosegregation data are available for NM_006164.4:c.100C>G in families with NFE2L2-related disease.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	No well-defined germline disease phenotype with high specificity is associated with NFE2L2 variants. The phenotype or family history cannot be evaluated for PP4.
PP5	Not met	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.	clinvar oncokb
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1 population databases. Allele frequency is well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1. Allele frequency is well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.
BS3	Not assessed	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.
BS4	Not assessed	No data are available on non-segregation of NM_006164.4:c.100C>G with disease in affected families.
BP1	Not assessed	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.
BP2	N/A	BP2 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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	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.
BP6	Not met	No reputable source has reported NM_006164.4:c.100C>G as benign. ClinVar Variation ID 3258027 has no classification.	clinvar
BP7	N/A	BP7 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.
BP3	N/A	BP3 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.
PM3	N/A	PM3 applies to variants detected in trans with a pathogenic variant in a recessive disorder. NFE2L2 is not established as causing an autosomal recessive disorder.
PM4	N/A	PM4 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.

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