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
NRAS
Final classification
Uncertain significance
NRAS c.176C>A · p.Ala59Asp
NRAS
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
Gene diagram
· NM_002524.4 · variants mapped to exon structure
NRAS
NM_002524.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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 supports · met
Sources & reference links