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
NRAS
Final classification
VUS
NRAS c.173C>T · p.Thr58Ile
NRAS
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 ↗
Gene diagram
· NM_002524.4 · variants mapped to exon structure
NRAS
NM_002524.4
Fetching transcript structure from UCSC…
Applied criteria · 5 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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