NM_002524.5:c.183A>T (p.Gln61His) in NRAS is a missense variant in the Switch II functional domain (HRAS 57-64), a critical GTPase region where pathogenic gain-of-function variants are well-established in the RASopathy spectrum.1 This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the RASopathy VCEP requirement for PM2 at moderate strength.2 Multiple different pathogenic missense variants at NRAS codon Q61 (Q61R, Q61K, Q61L) are established in the RASopathy spectrum, supporting PM5 at moderate strength.3 PP2 is applicable to all RASopathy genes per VCEP specification, reflecting the low rate of benign missense variation in these genes.4 REVEL predicts a damaging effect (score 0.742), and Q61 is a statistically significant cancer hotspot (cancerhotspots.org), supporting PP3 at supporting strength.5 This variant has been reported in ClinVar with conflicting classifications: Pathogenic (1 submitter, GeneDx) and Uncertain significance (1 submitter, Hospital for Sick Children). No expert panel review is available.6 NRAS Q61H is a well-established somatic oncogenic mutation reported 168 times in COSMIC and classified as Oncogenic (gain-of-function) by OncoKB. Functional studies per the VCEP-approved assay framework exist for NRAS but were not directly verified for this variant in the case materials.7
NRAS
Final classification
Likely Pathogenic
NRAS c.183A>T · p.Gln61His
NRAS
NM_002524.5:c.183A>T (p.Gln61His) in NRAS is a missense variant in the Switch II functional domain (HRAS 57-64), a critical GTPase region where pathogenic gain-of-function variants are well-established in the RASopathy spectrum.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PM5 moderate, PP2 supporting, PP3 supporting; combination = 3 moderate + 2 supporting, which maps to Likely Pathogenic.
Classification rationale
PM1PM2PM5PP2PP3
Likely Pathogenic
NRAS c.183A>T
PM1 + PM2 + PM5 + PP2 + PP3
→
Likely Pathogenic
Gene diagram
· NM_002524.5 · variants mapped to exon structure
NRAS
NM_002524.5
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 14 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
Residue Q61 is located within the Switch II functional domain (HRAS 57-64), which is explicitly listed as an approved PM1 functional domain in the RASopathy VCEP supplemental material (Alignment-with-PM1-domains). Q61 is also a statistically significant missense hotspot at cancerhotspots.org. NRAS is in the VCEP Group 1 analogous genes (HRAS, NRAS, KRAS).
VCEP PM1 domains: Switch II (HRAS 57-64) includes Q61applicable to NRAS via Group 1 analogy. cancerhotspots.org: residue Q61 is a statistically significant hotspot.
✓
PM2
moderate
Pathogenic
This variant is completely absent from all population databases surveyed (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0), satisfying the RASopathy VCEP requirement that the variant must be completely absent from all population databases.
Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (exomes/genomes). Absent from gnomAD-Canada v1.0.
✓
PM5
moderate
Pathogenic
Multiple different pathogenic missense changes at NRAS codon Q61 are established in the RASopathy spectrum (e.g., Q61R, Q61K, Q61L in HRAS/KRAS/NRAS). These are well-characterized gain-of-function pathogenic variants at the same residue. Q61H (His) is a non-conservative substitution concordant with the pathogenic direction of other Q61 missense changes. The VCEP mutual-exclusion rule (PM5 not to be used with PM1 when residue is a designated hotspot) does not apply here because Q61 is not individually designated as a mutational hotspot in the PM1 supplemental material — only the Switch II domain (57-64) is listed.
NRAS Q61RQ61KQ61L are established pathogenic variants at the same residue. Q61H is a non-conservative substitution (Gln→His
✓
PP2
supporting
Pathogenic
PP2 is explicitly applicable to all RASopathy genes described and curated by the VCEP, including NRAS. This is a missense variant in a gene where missense variants are a common mechanism of disease (gain-of-function), with a low rate of benign missense variation at critical residues.
VCEP RASopathy v1.0: PP2 is applicable to all RASopathy genes curated hereinincluding NRAS.
✓
PP3
supporting
Pathogenic
Multiple lines of computational evidence support a deleterious effect. REVEL score 0.742 predicts damaging. Residue Q61 is a statistically significant cancer hotspot (cancerhotspots.org). COSMIC reports 168 somatic occurrences at this position. OncoKB classifies as Oncogenic. SpliceAI max delta 0.00 indicates no cryptic splice impact. BayesDel 0.130 is discordant but REVEL and hotspot evidence together provide multiple independent lines of computational support.
REVEL 0.742 (pathogenic-leaning). cancerhotspots.org: statistically significant hotspot at Q61. COSMIC: 168 somatic counts. OncoKB: Oncogenic. SpliceAI: no splicing impact (max delta 0.00). BayesDel 0.130 (discordantbenign-leaning).
Assessed · not applied
Pathogenic
PS1
PS1 requires the same amino acid change (Q61H) to be previously established as pathogenic per VCEP criteria from a different nucleotide change.
PS2
No de novo occurrence report for NM_002524.5:c.183A>T (NRAS Q61H) with confirmed paternity in a RASopathy patient was identified in the case materials or literature reviewed.
PS3
The RASopathy VCEP has approved functional assays for NRAS (RAS Activation, MEK Activation, ERK Activation; PMIDs 19966803, 28594414, 21263000) at PS3_Supporting strength per assay.
PS4
No independent RASopathy-affected proband counts are available in the case materials.
PM6
No de novo occurrence report (with or without confirmed parentage) was identified in the case materials or reviewed literature for this variant in a RASopathy patient.
PP1
No co-segregation data or family studies are available in the case materials for this variant.
Benign
BA1
VCEP BA1 threshold is allele frequency >=0.05%.
BS1
VCEP BS1 threshold is allele frequency >=0.025%.
BS2
VCEP restricts BS2: due to variable expressivity and severity of RASopathies, general population data should not be used.
BS3
BS3 requires approved functional studies showing no damaging effect on protein function.
BS4
No segregation data (supporting or refuting co-segregation) is available in the case materials.
BP2
No data on whether this variant has been observed in trans with a pathogenic variant (for a dominant disorder) or in cis with a pathogenic variant is available in the case materials.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product.
BP5
No evidence of an alternate molecular basis for disease in a patient carrying this variant was identified in the case materials.
N/A · 9
PVS1 · PM3 · PM4 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
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.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 373003)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.742. BayesDel score = 0.13014.
Functional
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54736991, n = 168 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 8 PMIDs not cited in assessment
23103856 ↗
Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling.
ONCOKB
10574788 ↗
The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins.
ONCOKB
25148578 ↗
Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma.
ONCOKB
26090869 ↗
Molecular spectrum of BRAF, NRAS and KRAS gene mutations in plasma cell dyscrasias: implication for MEK-ERK pathway activation.
ONCOKB
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
35101336 ↗
Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).
CLINVAR
23619274 ↗
American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
CLINVAR