The NRAS c.176C>A (p.Ala59Asp, p.A59D) variant has been observed in somatic cancers in COSMIC (COSV54738004, 12 occurrences) and has been reported in ClinVar as Likely pathogenic by 1 clinical laboratory.1 This variant is absent from gnomAD controls, with 0/1,611,062 alleles in gnomAD v4.1 and no observation in gnomAD v2.1, supporting PM2_Supporting and arguing against a benign population frequency threshold.2 The variant is located in the NRAS Switch II domain (amino acids 57-64), a critical and well-established functional region specified for PM1 in the NRAS RASopathy criteria, but no ClinGen-approved variant-specific functional assay result was identified to apply PS3.3 Computational evidence supports a deleterious missense effect because the REVEL score is 0.837, above the PP3 threshold of 0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.4
Final classification
Uncertain significance
PM1PM2PP3
NRAS
c.176C>A
p.Ala59Asp
This variant
The NRAS c.176C>A (p.Ala59Asp, p.A59D) variant has been observed in somatic cancers in COSMIC (COSV54738004, 12 occurrences) and has been reported in ClinVar as Likely pathogenic by 1 clinical laboratory.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS v2.3.0 final-classification framework; applied criteria are PM1 at Moderate strength, PM2 at Supporting strength, and PP3 at Supporting strength, a combination that does not meet any Pathogenic, Likely Pathogenic, Likely Benign, or Benign rule and therefore remains Uncertain significance.
Classification rationale
PM1PM2PP3
Uncertain significance
NRAS c.176C>A
PM1 + PM2 + PP3
→
Uncertain significance
3
cspec ↗vcep_a_l_i_g_n_m_e_n_t___w_i_t_h___p_m_1___d_o_m_a_i_n_s___p_p_t_xvcep_s_v_i___r_a_s_o_p_a_t_h_y___v_c_e_p___v_2___a_p_p_r_o_v_e_d___f_u_n_c_t_i_o_n_a_l___s_t_u_d_i_e_s
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 · 3 applied · 14 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PM1
moderate
Pathogenic
The p.Ala59Asp missense change lies within the NRAS Switch II region (amino acids 57-64), which is a critical and well-established functional domain specified for PM1 in the NRAS RASopathy criteria.
NRAS CSPEC lists Switch II (AA 57-64) as a PM1 domain.Local PM1 domain alignment material shows the Switch II domain mapped across RAS proteins.Ala59 falls within AA 57-64.
PM2
supporting
Pathogenic
This variant is absent from gnomAD controls, with 0/1,611,062 alleles in gnomAD v4.1 and no observation in gnomAD v2.1, which meets the NRAS PM2_Supporting rule requiring absence from controls.
gnomAD v2.1: absent.gnomAD v4.1: total AC 0, AN 1611062, AF 0.0; highest subpopulation AC 0, AN 74784, AF 0.0.
PP3
supporting
Pathogenic
Computational evidence supports a deleterious protein effect because the REVEL score is 0.837, which is above the NRAS PP3 threshold of 0.7, while SpliceAI shows no meaningful splice effect (max delta score 0.01), supporting a missense rather than splice mechanism.
REVEL score 0.837.SpliceAI max delta score 0.01.
Assessed · not applied
· 3 not met · 11 not assessed
Pathogenic
PS1
No evidence was identified showing that this nucleotide change produces the same amino acid substitution as a previously established pathogenic variant.
PS2
No confirmed de novo occurrence with phenotype and parental testing information was identified, so PS2 cannot be scored.
PS3
Approved functional assay types for NRAS are listed by the RASopathy VCEP, but no variant-specific result for p.Ala59Asp was identified in the available functional materials, so PS3 is not applied.
PS4
This variant has been reported in ClinVar and in somatic cancers in COSMIC, but no germline case-count or case-control data were identified to assign the RASopathy point-based PS4 criterion.
PM5
No codon-specific evidence was identified showing a different established pathogenic missense change at NRAS codon 59 or an applicable analogous residue position sufficient to assign PM5.
PM6
No assumed de novo case information without confirmed parentage was identified, so PM6 cannot be scored.
PP1
No segregation data were identified, so PP1 is not met.
Benign
BA1
Population frequency does not meet BA1 because the gnomAD v4.1 allele frequency is 0.0% (0/1,611,062), which is below the BA1 threshold of 0.05%.
BS1
Population frequency does not meet BS1 because the gnomAD v4.1 allele frequency is 0.0% (0/1,611,062), which is below the BS1 threshold of 0.025%.
BS2
No data were identified showing this variant in unaffected individuals in a manner that would support BS2.
BS4
No non-segregation data were identified, so BS4 is not met.
BP2
No data were identified showing this variant in cis or trans with an alternative molecular explanation for the phenotype, so BP2 is not applied.
BP4
Computational evidence does not support BP4 because the REVEL score is 0.837, which is above the benign threshold of 0.3.
BP5
No evidence was identified for an alternate molecular basis explaining the phenotype independent of this variant, so BP5 is not applied.
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
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1611062 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74784 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,611,062
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54738004, n = 12 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Whole-genome sequencing of patients with rare diseases in a national health syst
Found
Structured finding pending for this record — see source link.
Applied to
→PP3
supporting
Sources & reference links