The NRAS c.368G>A (p.Arg123Lys) variant has not been observed in COSMIC and is reported in ClinVar as uncertain significance, including an expert panel submission from the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting the NRAS RASopathy VCEP PM2_Supporting rule.2 The reviewed RASopathy VCEP functional study materials identify approved assay types for NRAS, but no variant-specific approved assay result for p.Arg123Lys was identified, so PS3 is not currently supported.3 In silico evidence supports a deleterious missense effect, with REVEL 0.759 above the NRAS RASopathy VCEP PP3 threshold of 0.7, BayesDel 0.166482 directionally consistent with a damaging prediction, and SpliceAI predicting no significant splice impact with a maximum delta score of 0.00.4
NRAS
Final classification
VUS
NRAS c.368G>A · p.Arg123Lys
NRAS
The NRAS c.368G>A (p.Arg123Lys) variant has not been observed in COSMIC and is reported in ClinVar as uncertain significance, including an expert panel submission from 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: PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3
VUS
NRAS c.368G>A
PM2 + PP3
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
4
revelbayesdelspliceai ↗cspec ↗
Gene diagram
· NM_002524.4 · variants mapped to exon structure
NRAS
NM_002524.4
Fetching transcript structure from UCSC…
Applied criteria · 2 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 Uncertain significance (4 clinical laboratories) and as Uncertain Significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.759. BayesDel score = 0.166482.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NRAS, a GTPase, is mutated in a diverse range of cancers, most frequently in melanoma and thyroid cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links