Variant classification summary

NM_002524.5:c.35G>T

NRAS · NP_002515.1:p.(Gly12Val) · NM_002524.5

GRCh37: chr1:115258747 C>A · GRCh38: chr1:114716126 C>A

Gene: NRAS Transcript: NM_002524.5

Final call

Pathogenic

PS1 strong PS3 moderate PM1 moderate PM2 supporting PM5 strong PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.5

Protein

NP_002515.1:p.(Gly12Val)

gnomAD AF

6.195886674754365e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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

3

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).

4

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

5

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.

6

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

7

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

8

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

Final determination: Rule5 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

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	PVS1 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.	cspec
PS1	Met	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.	clinvar cspec oncokb
PS2	Not assessed	No de novo occurrence data with confirmed maternity and paternity was identified for NM_002524.5:c.35G>T in the available evidence.
PS3	Met	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.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	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.	clinvar
PS5	N/A	PS5 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.
PM1	Met	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.	cspec vcep_alignment_with_pm1_domains_pptx PMID:9219684
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	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.	clinvar cspec oncokb
PM6	Not assessed	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.
PP1	Not assessed	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.
PP2	N/A	Declared Not Applicable by the ClinGen RASopathy VCEP because the missense z-score is <3.09 in gnomAD for NRAS.	cspec
PP3	Met	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.	revel bayesdel spliceai cspec
PP4	N/A	Declared Not Applicable by the ClinGen RASopathy VCEP for NRAS.	cspec
PP5	N/A	Declared Not Applicable by the ClinGen RASopathy VCEP for NRAS.	cspec
BA1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	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.
BS3	N/A	Declared Not Applicable by the ClinGen RASopathy VCEP. All approved functional assays are assessed for PS3 only; BS3 is not applied for this gene.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	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.
BP1	N/A	BP1 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.	cspec
BP2	Not assessed	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.
BP4	Not met	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.	revel bayesdel cspec
BP5	Not assessed	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.
BP6	N/A	Declared Not Applicable by the ClinGen RASopathy VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	BP7 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.	cspec

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