Variant classification summary

NM_002524.4:c.34G>T

NRAS · NP_002515.1:p.(Gly12Cys) · NM_002524.4

GRCh37: chr1:115258748 C>A · GRCh38: chr1:114716127 C>A

Gene: NRAS Transcript: NM_002524.4

Final call

Pathogenic

PS1 strong PM1 moderate PM2 supporting PM5 moderate PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.4

Protein

NP_002515.1:p.(Gly12Cys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002524.4:c.34G>T (p.Gly12Cys) in NRAS is a missense variant affecting codon 12 in the P-loop (AA 10-17), a critical GTP-binding domain recognized by the RASopathy VCEP.

2

The p.Gly12Cys amino acid change is a well-established pathogenic alteration in NRAS and homologous RAS genes, meeting PS1 at Strong strength.

3

The variant lies within the P-loop functional domain (PM1, Moderate) and represents a missense change at a codon where other pathogenic missense variants are established (PM5, Moderate).

4

The variant is absent from all gnomAD population databases, meeting PM2 at Supporting strength.

5

REVEL score of 0.773 supports a deleterious effect, meeting PP3 at Supporting strength.

6

No de novo, cosegregation, case-count, or functional assay data from VCEP-approved platforms were available for this variant; PS2, PS3, PS4, PM6, PP1, BS2, BS4, BP2, and BP5 remain unassessed.

Final determination: Rule7 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 not applicable for NRAS under the RASopathy VCEP v2.3.0. This is a missense variant (c.34G>T, p.Gly12Cys) and does not fall into null-variant buckets (nonsense, frameshift, canonical splice). The VCEP explicitly marks PVS1 as Not Applicable for this gene.	cspec
PS1	Met	The variant produces p.Gly12Cys in NRAS, which is a well-established pathogenic amino acid change at codon 12 in RAS genes. The same residue (G12) is a recurrent oncogenic hotspot, and multiple NRAS G12 missense changes are classified as pathogenic. The RASopathy VCEP v2.3.0 assigns PS1 at Strong when the same amino acid change has been previously established as pathogenic, applicable across HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2.	clinvar oncokb cspec
PS2	Not assessed	No de novo occurrence data for NRAS G12C in a patient with a RASopathy phenotype was identified in any reviewed publication. De novo evidence with confirmed parentage is required to apply this criterion under the RASopathy VCEP.
PS3	Not assessed	No functional assay data from VCEP-approved assay platforms (RAS Activation, MEK Activation, ERK Activation) were identified for NRAS G12C in the reviewed publications. The VCEP-approved functional studies for NRAS cite PMIDs 19966803, 28594414, and 21263000, none of which were available for full-text review in this case. OncoKB notes Likely Gain-of-function based on curated somatic literature, but this does not independently satisfy the VCEP functional assay requirements for germline PS3 application.	oncokb vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	No proband count data specific to NRAS G12C in a RASopathy/germline context was identified in the reviewed publications. The VCEP PS4 criterion requires point-based scoring based on proband counts with RASopathy phenotypes, but no such counts were extractable from the available evidence. Somatic observations (COSMIC n=273; 1 colorectal cancer patient in PMID 33637626) are not directly applicable to germline PS4.
PS5	N/A	PS5 is not defined in the ClinGen RASopathy Expert Panel Specifications for NRAS Version 2.3.0. This criterion is not part of the VCEP framework for this gene.	cspec
PM1	Met	The variant affects codon 12 (p.Gly12Cys), which lies within the P-loop (amino acids 10-17), a critical and well-established functional domain recognized by the RASopathy VCEP. Codon 12 is a statistically significant mutational hotspot without benign variation.	cspec oncokb vcep_alignment_with_pm1_domains_pptx
PM2	Met	The variant is absent from all gnomAD population datasets (v2.1, v4.1, and gnomAD-Canada v1.0), satisfying the RASopathy VCEP requirement that the variant must be absent from controls.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Met	At least one other pathogenic missense change at the same codon (G12) has been established in NRAS. NRAS G12D, G12V, G12S, G12A, and G12R are well-documented pathogenic variants in both somatic and germline contexts. The RASopathy VCEP assigns PM5 at Moderate strength when one [likely] pathogenic residue change exists at the same codon.	cspec clinvar
PM6	Not assessed	No assumed de novo data without confirmation of parentage was identified for this variant in any reviewed publication. The RASopathy VCEP applies point-based scoring for PM6 but requires case-level data that was not available.
PP1	Not assessed	No cosegregation data was identified for this variant. The RASopathy VCEP requires ≥3 informative meioses for Supporting, ≥5 for Moderate, and ≥7 for Strong. No family studies were available for review.
PP2	N/A	The RASopathy VCEP v2.3.0 specifies PP2 as Not Applicable because the missense Z-score for NRAS is <3.09 in gnomAD.	cspec
PP3	Met	The REVEL score for this missense variant is 0.773, which meets the RASopathy VCEP threshold of ≥0.7 for PP3 at Supporting strength. SpliceAI predicts no splice impact (max delta = 0.00), consistent with a missense effect.	revel spliceai cspec
PP4	N/A	The RASopathy VCEP v2.3.0 specifies PP4 as Not Applicable; phenotype specificity is assessed through PS4 instead.	cspec
PP5	N/A	The RASopathy VCEP v2.3.0 specifies PP5 as Not Applicable for this VCEP, consistent with ClinGen SVI VCEP Review Committee recommendations.	cspec
BA1	Not met	The variant is absent from gnomAD. The RASopathy VCEP BA1 threshold requires a gnomAD filtering allele frequency ≥0.05%, which is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD. The RASopathy VCEP BS1 threshold requires a gnomAD filtering allele frequency ≥0.025%, which is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No data on healthy adult individuals carrying NRAS G12C was identified. The RASopathy VCEP requires observation in healthy homozygote/heterozygote individuals for BS2 application.
BS3	N/A	The RASopathy VCEP v2.3.0 specifies BS3 as Not Applicable for this gene.	cspec
BS4	Not assessed	No lack-of-segregation data was identified for this variant. The RASopathy VCEP requires only one informative meiosis for BS4 at Strong, but no family studies were available for review.
BP1	N/A	BP1 under the RASopathy VCEP applies only to 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. This variant is a missense substitution (c.34G>T, p.Gly12Cys) and does not qualify.	cspec
BP2	Not assessed	No data on an alternative molecular cause of a RASopathy in the same gene or in cis/trans with a pathogenic variant was identified for this case.
BP4	Not met	The REVEL score for this missense variant is 0.773, which exceeds the RASopathy VCEP BP4 threshold of ≤0.3. Multiple lines of computational evidence suggest a deleterious effect, and BP4 is not met.	revel bayesdel spliceai cspec
BP5	Not assessed	No data on an alternative molecular cause of disease in a different gene was identified for this case.
BP6	N/A	The RASopathy VCEP v2.3.0 specifies BP6 as Not Applicable for this VCEP, consistent with ClinGen SVI VCEP Review Committee recommendations.	cspec
BP7	N/A	BP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This variant is a missense substitution (c.34G>T, p.Gly12Cys) and does not qualify.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a substitution variant and the RASopathy VCEP specifies no known benign repetitive areas in RASopathy genes.	cspec
PM3	N/A	PM3 applies to recessive disorders with a variant detected in trans with a pathogenic variant. RASopathies are autosomal dominant, and the VCEP specifies PM3 as Not Applicable.	cspec
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This is a missense substitution and does not alter protein length.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.