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
Final classification
VUS
PM2PP3
NRAS
c.368G>A
p.Arg123Lys
This variant
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 ↗
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 · 2 applied · 15 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the NRAS RASopathy VCEP PM2 threshold requiring absence from controls.
gnomAD v2.1: absentgnomAD v4.1: absent
PP3
supporting
review
Pathogenic
Computational evidence supports a deleterious effect. REVEL is 0.759, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available BayesDel score is 0.166482, which is directionally consistent with a damaging missense prediction.
REVEL 0.759SpliceAI max delta 0.00BayesDel 0.166482
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
PS1
No previously established pathogenic variant producing the same amino acid change, p.Arg123Lys, was identified in the reviewed evidence, so PS1 is not supported.
PS2
No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be assessed from the available evidence.
PS3
The reviewed RASopathy VCEP functional study materials list approved assay types for NRAS, but no variant-specific approved assay result for p.Arg123Lys was identified, so PS3 is not currently supported.
PS4
This variant is absent from gnomAD, satisfying the PM2 prerequisite for PS4 consideration, but no usable count of unrelated affected individuals or point-based case evidence was identified, so PS4 cannot be assessed.
PM1
Residue Arg123 is outside the NRAS RASopathy VCEP PM1 domains (P-loop amino acids 10-17, Switch I amino acids 25-40, Switch II amino acids 57-64, and SAK amino acids 145-156), so PM1 is not met.
PM5
No different pathogenic or likely pathogenic missense change at codon 123 was identified in the reviewed evidence, so PM5 is not supported.
PM6
No unconfirmed de novo report with sufficient phenotype context was identified for this variant, so PM6 cannot be assessed from the available evidence.
PP1
No segregation data were identified for this variant, so PP1 cannot be assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the NRAS RASopathy VCEP BA1 threshold of 0.05%, so BA1 is not met.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the NRAS RASopathy VCEP BS1 threshold of 0.025%, so BS1 is not met.
BS2
No observations of this variant in unaffected individuals suitable for NRAS RASopathy VCEP BS2 scoring were identified, so BS2 is not met.
BS4
No non-segregation data or unaffected carrier relatives were identified for this variant, so BS4 cannot be assessed.
BP2
No evidence was identified that this variant occurs in cis or trans with an alternative pathogenic RASopathy variant with sufficient phenotype context, so BP2 cannot be assessed.
BP4
Computational evidence does not support a benign interpretation.
BP5
No alternative molecular explanation or phenotype-discordant diagnosis was identified that would support BP5, so this criterion cannot be assessed.
N/A · 11
PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · 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 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