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NRAS
Final classification
VUS
PM1PM2PP3
NRAS
c.182A>T
p.Gln61Leu
missense · exon 3
Gene context NCBI Gene ↗ OncoKB ↗

NRAS encodes a membrane-associated GTPase that shuttles between the Golgi apparatus and the plasma membrane, where it helps regulate the MAPK and PI3K signaling pathways that control cell growth and division. It is a well-known oncogene: when overactive, it drives excessive cellular proliferation, and it is frequently altered in melanoma, thyroid cancer, ovarian cancer, and hematological cancers, where its activity can also contribute to resistance to some targeted cancer therapies. NRAS alterations are additionally associated with Noonan syndrome, autoimmune lymphoproliferative syndrome, and juvenile myelomonocytic leukemia.

This variant

NRAS is a well-known oncogene in melanoma, thyroid, ovarian, and hematological cancers, and Gln61 is a classic oncogenic hotspot (OncoKB: Oncogenic, gain-of-function). For germline RASopathy interpretation, however, the evidence for this variant - location in the Switch II domain, absence from gnomAD, and a high REVEL score - reaches only moderate-to-supporting strength. That falls short of the pathogenic thresholds, so the variant remains a VUS: germline pathogenicity is not established, though clinical significance cannot be excluded.

Transcript
NM_002524.5
HGVS · transcript:coding
NM_002524.5:c.182A>T
GRCh38
chr1:114713908 T>A
GRCh37
chr1:115256529 T>A
Basis VUS under ClinGen RASopathy VCEP v2.3: PM1 (moderate), PM2 and PP3 (supporting) total 4 SVI points (VUS range 0-5), satisfying no pathogenic or benign rule. ▾
VUS under ClinGen RASopathy VCEP v2.3: PM1 (moderate), PM2 and PP3 (supporting) total 4 SVI points (VUS range 0-5), satisfying no pathogenic or benign rule.
Classification rationale
PM1PM2PP3 VUS
NRAS c.182A>T missense · exon 3

PM1 (Moderate): codon 61 lies in the Switch II (residues 57-64) critical functional domain. PM2 (Supporting): the variant is absent from gnomAD v2.1 and v4.1. PP3 (Supporting): REVEL score 0.897 exceeds the >=0.7 threshold. Total: 4 SVI points (VUS range 0-5) under ClinGen RASopathy VCEP v2.3, with no pathogenic or benign rule satisfied, yielding a VUS.

PM1 + PM2 + PP3 → VUS
Gene diagram · NM_002524.5 · variants mapped to exon structure
NRAS NM_002524.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength Supporting Moderate Strong Very strong
✓
PM1 moderate Pathogenic
Met (Moderate): codon 61 falls within the Switch II (SW2, residues 57-64) critical functional domain.
cspec (NRAS VCEP v2.3): PM1 rule = 'Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).'Case summary normalization: NP_002515.1:p.(Gln61Leu) places the variant at residue 61, within the VCEP-defined SW2 domain boundary (AA 57-64).Final classification framework instructionsToUse for PM1: 'Applicable for observed analogous residue positions in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5_Strong is applied to avoid overweighting.'
cspec ↗
✓
PM2 supporting Pathogenic
Met (Supporting): absent from both gnomAD v2.1 and v4.1 population databases.
The governing NRAS RASopathy Expert Panel specification defines PM2 at supporting strength when the variant is absent from controls in gnomAD.gnomAD v2.1 and gnomAD v4.1 each report NM_002524.5:c.182A>T (NRAS p.Gln61Leu) as absent.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
✓
PP3 supporting Pathogenic
Met (Supporting): REVEL score 0.897 exceeds the >=0.7 VCEP threshold for missense variants.
VCEP (ClinGen RASopathy Expert Panel NRAS CSPEC v2.3) PP3 rule: 'For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.' Default strength Supporting.Local REVEL v1.3 lookup for chr1:114713908 T>A returns REVEL score = 0.897, which is >= the VCEP's 0.7 missense threshold for PP3.
cspec ↗
Assessed · not applied · 3 not met · 11 not assessed
Pathogenic
PS1 Not assessed: no established germline pathogenic classification of Gln61Leu at NRAS codon 61 or an analogous paralog residue was available.
PS2 Not assessed: no de novo occurrence with both maternity and paternity confirmed was reported.
PS3 Not assessed: no quantitative results from an approved functional assay (e.g., RAS/MEK/ERK activation) for this variant were available.
PS4 Not assessed: no germline case series or case-control data for p.Gln61Leu with proband counts was available.
PM5 Not assessed: no established pathogenic or likely pathogenic change at NRAS codon 61 (e.g., Gln61Arg/Lys) was documented.
PM6 Not assessed: no affected individual with the variant absent from parents was reported.
PP1 Not assessed: no family segregation data or informative meioses were available.
Benign
BA1 Not met: the variant is absent from gnomAD, far below the >=0.05% allele frequency threshold.
BS1 Not met: the variant is absent from gnomAD, far below the >=0.025% allele frequency threshold.
BS2 Not assessed: no observations of the variant in healthy or unaffected individuals were available.
BS4 Not assessed: no informative non-segregation observation in an affected family member was available.
BP2 Not assessed: no alternate molecular cause or cis/trans phase evidence was available.
BP4 Not met: REVEL score 0.897 is far above the <=0.3 threshold required for BP4.
BP5 Not assessed: no documented alternate molecular diagnosis fully explaining the phenotype was available.
N/A · 11 PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 375874)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.897. BayesDel score = 0.356835.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54736624, n = 421 times).
Hotspots
This variant lies in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 8 PMIDs not cited in assessment
10574788 ↗ The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins. ONCOKB
19492075 ↗ Combined targeting of BRAF and CRAF or BRAF and PI3K effector pathways is required for efficacy in NRAS mutant tumors. ONCOKB
20194776 ↗ Allosteric modulation of Ras positions Q61 for a direct role in catalysis. ONCOKB
23515407 ↗ Characteristics of lung cancers harboring NRAS mutations. ONCOKB
26619011 ↗ Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. ONCOKB
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
33056981 ↗ Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations. CLINVAR
26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR