The NRAS NM_002524.4:c.173C>T (NP_002515.1:p.Thr58Ile; NP_002515.1:p.T58I) variant has been observed in somatic cancers in COSMIC (COSV54738937, n=4) and has been reported in ClinVar as pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.2 In the RASopathy VCEP-approved functional studies resource, NRAS p.Thr58Ile is listed as a pathogenic or likely pathogenic validation control across multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays, supporting an abnormal activating effect.3 Computational evidence supports a damaging missense effect, with REVEL 0.959 and BayesDel 0.45829, while SpliceAI predicts no significant splice impact (maximum delta score 0.01).4
Final classification
VUS
PS3PM1PM2PP3PP5
NRAS
c.173C>T
p.Thr58Ile
This variant
The NRAS NM_002524.4:c.173C>T (NP_002515.1:p.Thr58Ile; NP_002515.1:p.T58I) variant has been observed in somatic cancers in COSMIC (COSV54738937, n=4) and has been reported in ClinVar as pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PS3PM1PM2PP3PP5
VUS
NRAS c.173C>T
PS3 + PM1 + PM2 + PP3 + PP5
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
revelbayesdelspliceai ↗
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.
Gene diagram
· NM_002524.4 · variants mapped to exon structure
NRAS
NM_002524.4
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 13 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 · 5
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
review
Pathogenic
In the RASopathy VCEP-approved functional studies resource, NRAS p.Thr58Ile is listed among pathogenic or likely pathogenic validation controls in multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays. These data support an abnormal functional effect consistent with pathogenic activation.
NRAS p.T58I appears as a pathogenic/likely pathogenic validation control in approved RAS activationMEK activationand ERK activation assays.
PM1
moderate
review
Pathogenic
The p.Thr58Ile change lies in the NRAS Switch II region (amino acids 57-64), which the NRAS RASopathy VCEP designates as a critical and well-established functional domain for PM1.
Thr58 falls within the VCEP-defined SW2 domain spanning amino acids 57-64.
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the NRAS RASopathy VCEP PM2 requirement that the variant be absent from controls.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
PP3
supporting
review
Pathogenic
For this missense variant, the REVEL score is 0.959, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7. BayesDel is also positive at 0.45829, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, supporting a missense rather than splice-driven damaging effect.
REVEL score 0.959.BayesDel score 0.45829.SpliceAI max delta score 0.01.
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No previously established pathogenic variant causing the same amino acid change from a different nucleotide change was identified in the available evidence.
PS2
This variant has been reported in germline disease databases, but no confirmed de novo occurrence with both maternity and paternity established was identified in the available evidence.
PS4
This variant has been observed in affected submissions in ClinVar, but the available evidence does not provide the proband counts or point-based case evidence needed for PS4 under the NRAS RASopathy VCEP framework.
PM5
No different pathogenic or likely pathogenic missense change at the same codon was identified in the available evidence to support PM5.
PM6
No assumed de novo occurrence without confirmed maternity and paternity was documented in the available evidence, so PM6 was not applied.
PP1
No segregation data were identified to support or refute cosegregation with disease.
Benign
BA1
This variant is absent from gnomAD and therefore is below the BA1 stand-alone benign threshold of 0.05%.
BS1
This variant is absent from gnomAD and therefore is below the BS1 strong benign threshold of 0.025%.
BS2
No observations in clearly unaffected individuals were identified to support BS2.
BS4
No nonsegregation data were identified to support BS4.
BP2
No evidence was identified that this variant was observed with an alternative molecular explanation meeting the VCEP BP2 point-based framework.
BP4
Computational evidence does not support a benign interpretation.
BP5
No alternative molecular cause explaining the phenotype was identified to support BP5.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.959. BayesDel score = 0.45829.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54738937, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links