Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_002524.4 | Alternative | 4454 nt | 255–824 |
| NM_002524.5 | MANE Select | 4326 nt | 132–701 |
| NM_002524.3 | Alternative | 4461 nt | 255–824 |
| NM_002524.2 | Alternative | 1963 nt | 254–823 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The NRAS Q61R variant has been functionally characterized as oncogenic. It is located in the switch II region of the catalytic domain, leading to constitutive activation of the protein due to impaired GTP hydrolysis. Functional studies demonstrate that this mutation results in increased cell proliferation, tumor growth, and pathway activation in cancer cell lines. It is resistant to certain inhibitors but sensitive to MEK inhibitors, indicating its role in activating the MAPK signaling pathway.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 320 bp |
| Donor Loss (DL) | 0.0 | -111 bp |
| Acceptor Gain (AG) | 0.01 | 59 bp |
| Donor Gain (DG) | 0.0 | 277 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion) in a gene where loss-of-function is a known mechanism of disease'. The evidence for this variant shows: it is a missense change (Q61R), not a null variant. Therefore, this criterion is not applied.
PS1 (Strong)
According to VCEP guidelines, rule for PS1 is: 'Strong Strength: Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous pathogenic residue positions in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2.'. The evidence for this variant shows: Q61R is a known pathogenic amino acid substitution at codon 61 in NRAS. Therefore, this criterion is applied at Strong strength because the same amino acid change is previously established as pathogenic.
PS2 (Not Applied)
According to VCEP guidelines, rule for PS2 is: 'Very Strong Strength: Very Strong 4 Points. Modification Type: Strength (de novo)'. The evidence for this variant shows: de novo status has not been assessed. Therefore, this criterion is not applied.
PS3 (Moderate)
According to VCEP guidelines, rule for PS3 is: 'Moderate Strength: Moderate Two or more different approved assays. Modification Type: Disease-specific,Gene-specific,Strength.'. The evidence for this variant shows: multiple functional studies demonstrate constitutive activation of NRAS Q61R, increased signaling, and oncogenic transformation. Therefore, this criterion is applied at Moderate strength because two or more approved assays support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, rule for PS4 is: 'Strong Strength: Strong ≥5 points. Modification Type: Disease-specific (case-control data)'. The evidence for this variant shows: no case-control or point-based prevalence data provided. Therefore, this criterion is not applied.
PM1 (Moderate)
According to VCEP guidelines, rule for PM1 is: 'Moderate Strength: Moderate Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5). Modification Type: Gene-specific.'. The evidence for this variant shows: Q61R resides in the SW2 domain (AA 57-64) of NRAS. Therefore, this criterion is applied at Moderate strength because the variant is in a critical functional domain.
PM2 (Supporting)
According to VCEP guidelines, rule for PM2 is: 'Supporting Strength: Supporting The variant must be absent from controls (gnomAD). Modification Type: Strength.'. The evidence for this variant shows: Q61R is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.'. The evidence for this variant shows: no data on trans configuration with another variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions in non-repeat regions.'. The evidence for this variant shows: Q61R is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Moderate)
According to VCEP guidelines, rule for PM5 is: 'Moderate Strength: Moderate 1 [likely] pathogenic residue change at the same codon. Modification Type: Analogous Gene,Disease-specific.'. The evidence for this variant shows: other pathogenic substitutions at codon 61 (e.g., Q61K, Q61L) have been reported. Therefore, this criterion is applied at Moderate strength because a pathogenic residue change at the same position is established.
PM6 (Not Applied)
According to standard ACMG guidelines, rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity.'. The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, rule for PP1 is: 'Segregation in multiple affected family members in a gene definitively known to cause the disease.'. The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.'. The evidence for this variant shows: NRAS has numerous missense variants, but this criterion is gene-specific and not conclusively met here. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, rule for PP3 is: 'Supporting Strength: Supporting For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.'. The evidence for this variant shows: computational tools show mixed results with CADD 3.94 and SpliceAI 0.01. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.'. The evidence for this variant shows: no detailed phenotype provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, rule for PP5 is: 'Reputable source reports variant as pathogenic but evidence not available for independent evaluation.'. The evidence for this variant shows: ClinVar entries exist, but PP5 is no longer recommended by ACMG. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, rule for BA1 is: 'Stand Alone Strength: Stand Alone GnomAD filtering allele frequency ≥0.05%.'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, rule for BS1 is: 'Strong Strength: Strong GnomAD filtering allele frequency ≥0.025%.'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, rule for BS2 is: 'Observed in a healthy adult individual for a recessive (homozygous) or dominant (heterozygous) disorder with full penetrance at an early age.'. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, rule for BS3 is: 'Well-established functional studies show no damaging effect on protein/function.'. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, rule for BS4 is: 'Lack of segregation in affected members of a family.'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, rule for BP1 is: 'Supporting Strength: Supporting This rule has contraindications for use with RASopathies.'. The evidence for this variant shows: variant is missense with gain-of-function, not truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, rule for BP2 is: 'Observed in trans with a pathogenic variant or observed in cis with a pathogenic variant without contributing to phenotype.'. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, rule for BP3 is: 'In-frame deletions/insertions in repetitive regions without a known function.'. The evidence for this variant shows: not an indel in repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, rule for BP4 is: 'Supporting Strength: Supporting For missense variants: REVEL ≤0.3.'. The evidence for this variant shows: mixed computational results and VCEP computational threshold not clearly met. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.'. The evidence for this variant shows: no alternate molecular basis identified. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, rule for BP6 is: 'Reputable source reports variant as benign but evidence not available.'. The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, rule for BP7 is: 'Synonymous variant with no impact on splicing predicted.'. The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.