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LYFE SCIENCES
Project: HERA
NM_002524.4:c.368G>A
p.Arg123Lys  ·  NRAS
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.759. BayesDel score = 0.166482.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR123
Hotspots ↗