NRASc.35G>TPathogenic

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Variant interpretation report

NRAS c.35G>T, p.(Gly12Val)

NM_002524.5:c.35G>T NP_002515.1:p.(Gly12Val) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About NRAS

No gene-level summary was recorded for this case.

Key facts

Condition: RASopathy
Inheritance: Autosomal dominant
Evidence used: 2 strong (pathogenic) · 2 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen NRAS VCEP v2.3.0
Other laboratories (ClinVar): 6 Pathogenic · 1 Likely pathogenic
Pipeline record: 19 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PS1 (strong): NM_002524.5:c.35G>T produces NP_002515.1:p.(Gly12Val), the same amino acid change as a previously well-established pathogenic variant in NRAS. G12V is a canonical oncogenic substitution documented in ClinVar as Pathogenic by multiple clinical laboratories and in COSMIC (n=183). Applicable per VCEP rule for observed analogous pathogenic residues in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2.
PS3 (moderate): NRAS G12V is listed as a pathogenic/likely pathogenic validation control in two VCEP-approved functional assay types: the RAS Activation Assay (approved PMIDs: 19966803, 28594414, 21263000) and the MEK Activation Assay (same PMIDs). Per the VCEP READ ME: two or more unique approved assay types for a given variant upgrades PS3 from Supporting to Moderate strength.
PM1 (moderate): The variant affects codon 12 (Gly12), which lies within the P-loop domain (amino acids 10-17), a critical and well-established functional domain per the RASopathy VCEP. The P-loop is essential for GTP binding and the variant lies within a statistically significant mutational hotspot with no benign variation.
PM2 (supporting): The variant is essentially absent from population controls. gnomAD v2.1: 0/251,484 alleles (0%). gnomAD v4.1: 1/1,613,974 alleles (0.00006%). gnomAD-Canada: 0 alleles. A single allele in gnomAD v4.1 is noted but does not negate PM2 at supporting strength under the VCEP rule requiring absence from controls.
PM5 (strong): Multiple different pathogenic missense variants exist at codon 12 (Gly12) in NRAS: G12D, G12S, G12C, G12A, and G12R are all well-established pathogenic substitutions at the same residue. This meets the VCEP PM5_Strong rule: ≥2 different pathogenic/likely pathogenic residue changes at the same codon observed in ≥5 probands.
PP3 (supporting): REVEL score is 0.787, which meets the VCEP PP3 threshold of ≥0.7 for missense variants. BayesDel score is 0.315. SpliceAI delta score is 0.00, indicating no predicted splice impact.

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 ClinGen NRAS VCEP v2.3.0. 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: 6 Benign evidence criteria: 0

Pathogenic criteria applied · 6

PS1Strong

PS1 · strong

NM_002524.5:c.35G>T produces NP_002515.1:p.(Gly12Val), the same amino acid change as a previously well-established pathogenic variant in NRAS. G12V is a canonical oncogenic substitution documented in ClinVar as Pathogenic by multiple clinical laboratories and in COSMIC (n=183). Applicable per VCEP rule for observed analogous pathogenic residues in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2.

PS3Moderate

PS3 · moderate

NRAS G12V is listed as a pathogenic/likely pathogenic validation control in two VCEP-approved functional assay types: the RAS Activation Assay (approved PMIDs: 19966803, 28594414, 21263000) and the MEK Activation Assay (same PMIDs). Per the VCEP READ ME: two or more unique approved assay types for a given variant upgrades PS3 from Supporting to Moderate strength.

PM1Moderate

PM1 · moderate

The variant affects codon 12 (Gly12), which lies within the P-loop domain (amino acids 10-17), a critical and well-established functional domain per the RASopathy VCEP. The P-loop is essential for GTP binding and the variant lies within a statistically significant mutational hotspot with no benign variation.

PM2Supporting

PM2 · supporting

The variant is essentially absent from population controls. gnomAD v2.1: 0/251,484 alleles (0%). gnomAD v4.1: 1/1,613,974 alleles (0.00006%). gnomAD-Canada: 0 alleles. A single allele in gnomAD v4.1 is noted but does not negate PM2 at supporting strength under the VCEP rule requiring absence from controls.

PM5Strong

PM5 · strong

Multiple different pathogenic missense variants exist at codon 12 (Gly12) in NRAS: G12D, G12S, G12C, G12A, and G12R are all well-established pathogenic substitutions at the same residue. This meets the VCEP PM5_Strong rule: ≥2 different pathogenic/likely pathogenic residue changes at the same codon observed in ≥5 probands.

PP3Supporting

PP3 · supporting

REVEL score is 0.787, which meets the VCEP PP3 threshold of ≥0.7 for missense variants. BayesDel score is 0.315. SpliceAI delta score is 0.00, indicating no predicted splice impact.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule5 (Pathogenic.Strong >=2) with applied criteria: PS1 strong, PS3 moderate, PM1 moderate, PM2 supporting, PM5 strong, PP3 supporting; maps to Pathogenic.

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

1 / 1,613,974 alleles

gnomAD v4.1: 1 / 1,613,974 alleles. Recorded AF 6.19589e-07. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251484 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

7 reported laboratory submissions

6 Pathogenic · 1 Likely pathogenic.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

183 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV54736974, n = 183 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen NRAS VCEP v2.3.0, with the data and sources behind each one.

26 criteria with recorded statuses: 6 met · 3 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_002524.5:c.35G>T (NP_002515.1:p.Gly12Val) is a missense variant in NRAS exon 2.

G12V is a well-established pathogenic substitution at a critical residue within the P-loop GTP-binding domain (amino acids 10-17).

This variant has been reported in ClinVar as Pathogenic by 6 clinical laboratories and Likely pathogenic by 1 (ClinVarID 40470), and is a recurrent somatic alteration in human cancers (COSMIC n=183; OncoKB: Oncogenic).

The variant is essentially absent from population databases (gnomAD v2.1: 0/251,484; v4.1: 1/1,613,974; gnomAD-Canada: absent).

G12V has been functionally characterized as an activating alteration in two VCEP-approved assay types (RAS Activation and MEK Activation), supporting a gain-of-function mechanism consistent with RASopathy pathogenesis.

Multiple different pathogenic missense variants exist at the same codon (G12D, G12S, G12C, G12A, G12R), supporting the functional importance of this residue.

In silico predictors support a deleterious effect (REVEL 0.787; BayesDel 0.315; SpliceAI delta 0.00).

Criteria met: PS1 (Strong), PS3 (Moderate), PM1 (Moderate), PM5 (Strong), PM2 (Supporting), PP3 (Supporting).

Met · 6

PS1 StrongNM_002524.5:c.35G>T produces NP_002515.1:p.(Gly12Val), the same amino acid change as a previously well-established pathogenic variant in NRAS. G12V is a canonical oncogenic substitution documented in ClinVar as Pathogenic by multiple clinical laboratories and in COSMIC (n=183). Applicable per VCEP rule for observed analogous pathogenic residues in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2. Details ▾Hide ▴

Evidence considered

ClinVar: Pathogenic by 6 clinical labs
Likely pathogenic by 1 (ClinVarID 40470)
COSMIC: reported 183 times in somatic cancers (COSV54736974)
OncoKB: classified as Oncogenic
Gain-of-function
VCEP PS1 rule: same amino acid change as previously established pathogenic variant

Sources

clinvar ↗cspec ↗oncokb ↗

PS3 ModerateNRAS G12V is listed as a pathogenic/likely pathogenic validation control in two VCEP-approved functional assay types: the RAS Activation Assay (approved PMIDs: 19966803, 28594414, 21263000) and the MEK Activation Assay (same PMIDs). Per the VCEP READ ME: two or more unique approved assay types for a given variant upgrades PS3 from Supporting to Moderate strength. Details ▾Hide ▴

Evidence considered

VCEP RAS Activation Assay: G12V listed as P/LP validation control
assay approved as PS3_Supporting
VCEP MEK Activation Assay: G12V listed as P/LP validation control
Two unique approved assay types = PS3_Moderate per VCEP READ ME

Sources

cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

PM1 ModerateThe variant affects codon 12 (Gly12), which lies within the P-loop domain (amino acids 10-17), a critical and well-established functional domain per the RASopathy VCEP. The P-loop is essential for GTP binding and the variant lies within a statistically significant mutational hotspot with no benign variation. Details ▾Hide ▴

Evidence considered

VCEP PM1: P-loop (AA 10-17) is a critical functional domain
PM1 domains alignment confirms G12 in P-loop
Hotspot analysis: residue is in a statistically significant mutational hotspot
PMID 9219684: structural basis of Gly12 role in GTPase activation

Sources

cspec ↗vcep_alignment_with_pm1_domains_pptxPMID:9219684 ↗

PM2 SupportingThe variant is essentially absent from population controls. gnomAD v2.1: 0/251,484 alleles (0%). gnomAD v4.1: 1/1,613,974 alleles (0.00006%). gnomAD-Canada: 0 alleles. A single allele in gnomAD v4.1 is noted but does not negate PM2 at supporting strength under the VCEP rule requiring absence from controls. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 0/251
484 alleles
gnomAD v4.1: 1/1
613
974 alleles (0.00006%)
gnomAD-Canada: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PM5 StrongMultiple different pathogenic missense variants exist at codon 12 (Gly12) in NRAS: G12D, G12S, G12C, G12A, and G12R are all well-established pathogenic substitutions at the same residue. This meets the VCEP PM5_Strong rule: ≥2 different pathogenic/likely pathogenic residue changes at the same codon observed in ≥5 probands. Details ▾Hide ▴

Evidence considered

G12D
G12S
G12C
G12A
G12R: well-established pathogenic variants at same codon
Multiple pathogenic residues at codon 12 documented in ClinVar and COSMIC
VCEP PM5_Strong: ≥2 different pathogenic residue changes at same codon

Sources

clinvar ↗cspec ↗oncokb ↗

PP3 SupportingREVEL score is 0.787, which meets the VCEP PP3 threshold of ≥0.7 for missense variants. BayesDel score is 0.315. SpliceAI delta score is 0.00, indicating no predicted splice impact. Details ▾Hide ▴

Evidence considered

REVEL: 0.787 (meets VCEP threshold ≥0.7)
BayesDel: 0.315
SpliceAI: max delta 0.00 (no splice impact)

Sources

revelbayesdelspliceai ↗cspec ↗

Not met · 3 · evaluated, threshold not reached

BA1 The VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. The variant frequency is 0% in gnomAD v2.1 and 0.00006% in gnomAD v4.1, far below the BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF: 0%
gnomAD v4.1 AF: 0.00006%
VCEP BA1 threshold: ≥0.05% — not met

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 The VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. The variant frequency is 0% in gnomAD v2.1 and 0.00006% in gnomAD v4.1, far below the BS1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF: 0%
gnomAD v4.1 AF: 0.00006%
VCEP BS1 threshold: ≥0.025% — not met

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP4 The VCEP BP4 threshold is REVEL ≤0.3 for missense variants. The REVEL score for this variant is 0.787, well above the benign threshold. Multiple in silico predictors support a deleterious effect. Details ▾Hide ▴

Evidence considered

REVEL: 0.787 (does not meet VCEP BP4 threshold ≤0.3)
BayesDel: 0.315

Sources

revelbayesdelcspec ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo occurrence data with confirmed maternity and paternity was identified for NM_002524.5:c.35G>T in the available evidence. Details ▾Hide ▴

Still missing

No de novo segregation or trio data available

PS4 The VCEP PS4 criterion uses point-based scoring requiring specific proband counts. While ClinVar documents 7 clinical laboratory submissions classifying this variant as Pathogenic (6) or Likely pathogenic (1), specific proband counts are not available to assign points under the VCEP scoring system. Details ▾Hide ▴

Evidence considered

ClinVar: 7 clinical laboratory submissions (6 Pathogenic
1 Likely pathogenic)
ClinVar submission audit: 5 usable for classification
3 with PMID trails

Still missing

Proband counts needed for VCEP point-based PS4 scoring
PMID 28594414 (Altmüller 2017
germline NRAS genotype-phenotype) likely contains relevant proband data but was not available as full text

Sources

clinvar ↗

PM6 No de novo observation without confirmed parentage was identified for this variant. PM6 under the VCEP uses point-based scoring requiring specific de novo events. Details ▾Hide ▴

Still missing

No de novo data available

PP1 No segregation data with informative meioses was identified for NM_002524.5:c.35G>T. The VCEP PP1 requires ≥3 informative meioses for supporting, ≥5 for moderate, and ≥7 for strong strength. Details ▾Hide ▴

Still missing

No segregation or family studies available

BS2 No data on healthy adult individuals carrying NM_002524.5:c.35G>T were identified. The VCEP BS2 uses point-based scoring for observations in healthy homozygotes or heterozygotes. Details ▾Hide ▴

Still missing

No healthy adult carrier data available

BS4 No segregation data demonstrating lack of segregation with disease was identified. The VCEP BS4 requires only one informative meiosis showing the variant does NOT segregate with a RASopathy phenotype. Details ▾Hide ▴

Still missing

No segregation data available to evaluate BS4

BP2 No evidence of an alternative molecular cause of a RASopathy in the same gene was identified. The VCEP BP2 uses point-based scoring for observations in trans or cis with a pathogenic variant. Details ▾Hide ▴

Still missing

No data on co-occurring pathogenic variants in NRAS

BP5 No evidence of an alternative molecular cause of disease in a different gene was identified. The VCEP BP5 uses point-based scoring for alternative molecular diagnoses explaining the phenotype. Details ▾Hide ▴

Still missing

No data on alternative molecular diagnoses

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 VCEPPVS1 is declared Not Applicable by the ClinGen RASopathy VCEP for NRAS. This is a missense variant (NP_002515.1:p.Gly12Val), not a null variant. Details ▾Hide ▴

Evidence considered

VCEP declares PVS1 Not Applicable for NRAS

Sources

cspec ↗

PP2 VCEPDeclared Not Applicable by the ClinGen RASopathy VCEP because the missense z-score is <3.09 in gnomAD for NRAS. Details ▾Hide ▴

Evidence considered

VCEP declares PP2 Not Applicable

Sources

cspec ↗

PP4 VCEPDeclared Not Applicable by the ClinGen RASopathy VCEP for NRAS. Details ▾Hide ▴

Evidence considered

VCEP declares PP4 Not Applicable

Sources

cspec ↗

PP5 VCEPDeclared Not Applicable by the ClinGen RASopathy VCEP for NRAS. Details ▾Hide ▴

Evidence considered

VCEP declares PP5 Not Applicable

Sources

cspec ↗

BS3 VCEPDeclared Not Applicable by the ClinGen RASopathy VCEP. All approved functional assays are assessed for PS3 only; BS3 is not applied for this gene. Details ▾Hide ▴

Evidence considered

VCEP declares BS3 Not Applicable
PS3/BS3 functional evidence is unidirectional (PS3 only) for gain-of-function RASopathy variants

Sources

cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

BP1 N/ABP1 under the RASopathy VCEP is specifically for truncating variants (nonsense, frameshift, canonical splice site, initiation codon, whole gene or multi-exon deletion) in genes where the disease mechanism is gain-of-function. NM_002524.5:c.35G>T is a missense variant, not a truncating variant. Details ▾Hide ▴

Evidence considered

VCEP BP1 only applies to truncating variants
this is a missense variant (G12V)

Sources

cspec ↗

BP6 VCEPDeclared Not Applicable by the ClinGen RASopathy VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴

Evidence considered

VCEP declares BP6 Not Applicable

Sources

cspec ↗

BP7 N/ABP7 applies only to synonymous (silent) variants or intronic variants outside canonical splice sites with no predicted splice impact. NM_002524.5:c.35G>T is a missense variant producing p.Gly12Val, not a synonymous variant. Details ▾Hide ▴

Evidence considered

BP7 is for synonymous variants
this is a missense variant

Sources

cspec ↗

PS5 N/APS5 is not included in the ClinGen RASopathy VCEP criteria for NRAS. Under generic ACMG/AMP, no reputable source reporting this variant as pathogenic with unavailable evidence was identified. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: NRAS
Transcript: NM_002524.5
Coding (HGVS c.): NM_002524.5:c.35G>T
Protein (HGVS p.): NP_002515.1:p.(Gly12Val)
GRCh38: chr1:114716126 C>A
GRCh37: chr1:115258747 C>A
ClinVar: 40470, 3029607, 39648
COSMIC: COSV54736974

Gene diagram

Every interpreted variant in NRAS, mapped onto the exon structure of NM_002524.5. Select a row to find it on the plot.

NRASNM_002524.5

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 NRAS — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1 / 1,613,974 alleles AF 6.2e-07 · 0 homozygotes

gnomAD v2.1 0 / 251,484 alleles AF 0 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,974 alleles · 0 hom

European (non-Finnish)1 / 1,179,846

8.5e-07

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 0 · 0 / 251,484 alleles · 0 hom

No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19589e-07; MAF= 0.00006%, 1/1613974 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47568e-07; MAF= 0.00008%, 1/1179846 alleles, homozygotes = 0).

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +0 bp

0.000

SpliceAI acceptor gainat +51 bp

0.000

SpliceAI donor lossat +1 bp

0.000

SpliceAI donor gainat -76 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.010

Other predictors

REVEL: 0.787
BayesDel: 0.315

How the predictions were used

Evidence considered

REVEL: 0.787 (meets VCEP threshold ≥0.7)
BayesDel: 0.315
SpliceAI: max delta 0.00 (no splice impact)

Sources

revelbayesdelspliceai ↗cspec ↗

Evidence considered

REVEL: 0.787 (does not meet VCEP BP4 threshold ≤0.3)
BayesDel: 0.315

Sources

revelbayesdelcspec ↗

Evidence considered

BP7 is for synonymous variants
this is a missense variant

Sources

cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.787. BayesDel score = 0.314876.

6 paper records listed. 3 cited in the classification.

Cited in the classification

RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia.

Kim WI et al. · 2009 Jan 29

NRAS G12V was expressed in a Vav-tTA-driven repressible transgenic mouse model crossed with Mll-AF9 knock-in mice. Conditional repression of NRAS G12V induced apoptosis in AML cells and reduced peripheral WBC counts, demonstrating oncogene addiction. NRAS G12V expression contributed to AML maintenance by suppressing apoptosis and reducing differentiation.
→ PS3 Names this variant
PMID 18952898 ↗
Source detail

To study the oncogenic role of the NRAS oncogene (NRAS G12V) in the context of acute myeloid leukemia (AML), we used a Vav promoter-tetracycline transactivator (Vav-tTA)-driven repressible TRE-NRAS G12V transgene system in Mll-AF9 knock-in mice developing AML.

Location Abstract; Introduction paragraphs 1-2; Results throughout

Context Transgenic mouse model (Vav-tTA;TRE-NRAS G12V;Mll-AF9 triple transgenic); bone marrow transplantation into SCID mice; doxycycline-repressible system
ERK and PDE4 cooperate to induce RAF isoform switching in melanoma.

NRAS G12V was expressed in Melan-a mouse melanocytes to study RAF isoform switching. Oncogenic NRAS G12V transformed Melan-a cells and activated the MAPK pathway through CRAF rather than BRAF. CRAF depletion blocked ERK activation by NRAS G12V, whereas BRAF depletion did not. NRAS G12V induced constitutive ERK-mediated phosphorylation of BRAF on Ser151, inhibiting NRAS-BRAF interaction.
→ PS3 Names this variant
PMID 21478863 ↗
Source detail

Oncogenic NRAS G12V transformed Melan-a cells, and we observed that CRAF depletion with two different shRNAs blocked ERK activation by NRAS G12V, whereas BRAF depletion had no effect.

Location Results paragraphs 1-3; Figures 1a-c, 2a

Context Melan-a mouse melanocyte cell line; NRAS G12V overexpression; CRAF/BRAF shRNA knockdown; Flag-tagged NRAS G12V immunoprecipitation
The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.

Solved the three-dimensional structure of the H-Ras–RasGAP complex, demonstrating the structural basis for GTPase activation. Glycine-12 mutations (including G12P) are discussed as impairing GAP-accelerated GTP hydrolysis through steric interference with arginine-789 of GAP and glutamine-61 of Ras. The structural analysis explains why mutations at Gly12 activate oncogenic potential.
→ PM1 Does not name this variant
PMID 9219684 ↗
Source detail

Glycine-12 in the transition state mimic is within van der Waals distance of both arginine-789 of GAP-334 and glutamine-61 of Ras, and even its mutation to alanine would disturb the arrangements of residues in the transition state.

Location Abstract; Results section on Gly12 mutants; Figure 4; Discussion

Context X-ray crystallography of H-Ras-GDP-AlF3-GAP-334 complex at 2.5 Å resolution

Other recorded publications

Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

Developed a statistical algorithm to identify recurrently mutated residues across 11,119 human tumors. Identified 470 hotspot substitutions in 275 genes including KRAS G12 as the most frequently mutated hotspot. G12V is discussed only in the context of KRAS mutations across tumor types — NRAS G12V is not specifically identified or discussed in this paper.
Does not name this variant
PMID 26619011 ↗
Quoted passage
Gastric cancers, on the other hand, had the fewest G12V mutations among all KRAS G12-mutant tumor types, but the highest proportion of G12S.
Figure 3b (KRAS G12V distribution across tumor types)
Differential Outcomes in Codon 12/13 and Codon 61 NRAS-Mutated Cancers in the Phase II NCI-MATCH Trial of Binimetinib in Patients with NRAS-Mutated Tumors.

Phase II NCI-MATCH trial of binimetinib in NRAS-mutated tumors. Among 47 eligible patients, Gly12Val was identified in 4 patients (3 colorectal, 1 other). Codon 12/13 NRAS-mutated colorectal cancers had significantly shorter PFS and OS on binimetinib compared to codon 61-mutated tumors. The paper documents G12V as a recurrent NRAS mutation in clinical oncology.
Names this variant
PMID 33637626 ↗
Quoted passage
Gly12Val 3 (12.5%) 0 (0%) 1 (6.2%) 4 (8.5%)
Table 2 (Gly12Val: 4 patients); Results paragraph on codon distribution; Discussion paragraphs 5-8
Repressible transgenic model of NRAS oncogene-driven mast cell disease in the mouse.

Wiesner SM et al. · 2005

No paper-specific finding is recorded.

PMID 15831708 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,613,974 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 6 Pathogenic · 1 Likely pathogenic 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 ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 40470)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.787. BayesDel score = 0.314876.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54736974, n = 183 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.