Variant classification summary

NM_002524.4:c.176C>A

NRAS · NP_002515.1:p.(Ala59Asp) · NM_002524.4

GRCh37: chr1:115256535 G>T · GRCh38: chr1:114713914 G>T

Gene: NRAS Transcript: NM_002524.4

Final call

PM1 PM2_Supporting PP3

Variant details

Gene

NRAS

Transcript

NM_002524.4

Protein

NP_002515.1:p.(Ala59Asp)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

Final determination: PM1_Moderate with PM2_Supporting and PP3_Supporting does not reach the NRAS RASopathy Expert Panel threshold for likely pathogenicity and does not meet benign or likely benign criteria; the variant is therefore classified as of uncertain significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This missense variant does not create a predicted loss-of-function allele, and the NRAS RASopathy specification lists PVS1 as not applicable.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified showing that this nucleotide change produces the same amino acid substitution as a previously established pathogenic variant.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with phenotype and parental testing information was identified, so PS2 cannot be scored.	cspec literature_pass
PS3	Not assessed	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.	cspec vcep_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 oncokb
PS4	Not assessed	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.	cspec clinvar cosmic literature_pass
PM1	Met	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.	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_x
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the NRAS RASopathy specification.	cspec
PM4	N/A	This is a missense substitution and does not change protein length, so PM4 is not applicable.	cspec
PM5	Not assessed	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.	cspec clinvar
PM6	Not assessed	No assumed de novo case information without confirmed parentage was identified, so PM6 cannot be scored.	cspec literature_pass
PP1	Not assessed	No segregation data were identified, so PP1 is not met.	cspec literature_pass
PP2	N/A	PP2 is not applicable in the NRAS RASopathy specification.	cspec
PP3	Met	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.	cspec spliceai
PP4	N/A	PP4 is not applicable in the NRAS RASopathy specification.	cspec
PP5	N/A	PP5 is not applicable in the NRAS RASopathy specification.	cspec
BA1	Not met	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%.	cspec gnomad_v4
BS1	Not met	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%.	cspec gnomad_v4
BS2	Not assessed	No data were identified showing this variant in unaffected individuals in a manner that would support BS2.	cspec gnomad_v4
BS3	N/A	BS3 is not applicable in the NRAS RASopathy specification.	cspec
BS4	Not assessed	No non-segregation data were identified, so BS4 is not met.	cspec literature_pass
BP1	N/A	This criterion is reserved in the NRAS RASopathy specification for truncating variants in a gain-of-function disease context and does not apply to this missense variant.	cspec
BP2	Not assessed	No data were identified showing this variant in cis or trans with an alternative molecular explanation for the phenotype, so BP2 is not applied.	cspec literature_pass
BP3	N/A	BP3 is not applicable in the NRAS RASopathy specification.	cspec
BP4	Not met	Computational evidence does not support BP4 because the REVEL score is 0.837, which is above the benign threshold of 0.3.	cspec spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular basis explaining the phenotype independent of this variant, so BP5 is not applied.	cspec literature_pass
BP6	N/A	BP6 is not applicable in the NRAS RASopathy specification.	cspec
BP7	N/A	BP7 applies to synonymous, intronic, or non-coding variants with no predicted splice impact and does not apply to this missense variant.	cspec spliceai

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