Variant classification summary

NM_002524.5:c.183A>C

NRAS · NP_002515.1:p.(Gln61His) · NM_002524.5

GRCh37: chr1:115256528 T>G · GRCh38: chr1:114713907 T>G

Gene: NRAS Transcript: NM_002524.5

Final call

Likely Pathogenic

PM1 moderate PM2 supporting PM5 moderate PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.5

Protein

NP_002515.1:p.(Gln61His)

gnomAD AF

ClinVar

Tier I - Strong

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002524.5:c.183A>C (p.Gln61His) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting per VCEP).

2

Gln61 lies within the Switch II functional domain (AA 57-64), a critical and well-established functional domain defined by the RASopathy VCEP for GTP hydrolysis and effector interaction (PM1_Moderate per VCEP).

3

Multiple established pathogenic missense variants exist at the same codon (Q61R, Q61K, Q61L) in NRAS, satisfying PM5 at moderate strength per VCEP specifications.

4

REVEL in silico score of 0.742 meets the VCEP threshold for PP3 at supporting strength, predicting a deleterious amino acid substitution.

5

NM_002524.5:c.183A>C has been reported in ClinVar as Tier I - Strong (ClinVar ID 4530443) and classified as Oncogenic by OncoKB with gain-of-function mechanism. The variant is recurrent in somatic cancers (COSMIC n=149).

6

No VCEP-approved functional assay data, de novo observations, case-control studies, or segregation data are available for this variant in the germline RASopathy context.

Final determination: Rule14 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

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	CSPEC RASopathy VCEP v2.3.0 marks PVS1 as not applicable for NRAS. Additionally, NM_002524.5:c.183A>C is a missense substitution and does not fall into null-variant buckets (nonsense, frameshift, canonical splice).	cspec
PS1	Not assessed	PS1 per VCEP applies when the same amino acid change has been previously established as pathogenic regardless of nucleotide change across HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2. Q61H (p.Gln61His) is a well-established pathogenic variant in HRAS (Costello syndrome) and KRAS. However, the variant NM_002524.5:c.183A>C (p.Q61H) is itself the canonical change being assessed in this case. Whether PS1 can be applied when the variant under assessment produces the same amino acid change as a previously classified pathogenic variant at the same residue in a paralogous gene requires expert adjudication.	cspec oncokb
PS2	Not met	No de novo observation data available for NM_002524.5:c.183A>C in a RASopathy proband. ClinVar submissions provide no usable de novo reports.	clinvar
PS3	Not met	No VCEP-approved functional assay has directly tested NM_002524.5:c.183A>C (p.Q61H). The VCEP-approved functional studies for NRAS (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay, AKT Phosphorylation Assay) list validation controls that do not include Q61H (validation controls: G12V, I24N, T58I, G60E). While NRAS Q61H has been studied in the RD rhabdomyosarcoma cell line context (PMID:23103856), this is a somatic cancer model using an endogenous mutation, not a directed functional assay of the variant meeting VCEP standards for clinical germline interpretation.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:23103856
PS4	Not met	No proband counts available for NM_002524.5:c.183A>C in the RASopathy clinical context. ClinVar submissions total 0 usable for classification. No case-control or cohort data meeting VCEP PS4 point criteria were identified.	clinvar
PM1	Met	Gln61 (amino acid position 61) lies within the Switch II (SW2) functional domain (AA 57-64), one of four critical and well-established functional domains defined by the RASopathy VCEP (P-loop AA 10-17, SW1 AA 25-40, SW2 AA 57-64, SAK AA 145-156). SW2 is essential for GTP hydrolysis and effector interaction. Per VCEP, PM1 is applicable at moderate strength for variants in these domains.	cspec vcep_alignment_with_pm1_domains_pptx PMID:20194776 PMID:10574788 oncokb
PM2	Met	NM_002524.5:c.183A>C is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per VCEP RASopathy specifications, PM2 is applied at supporting strength when the variant is absent from gnomAD controls.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Met	Codon 61 in NRAS harbors multiple well-established pathogenic missense variants (Q61R, Q61K, Q61L) reported in ClinVar and the literature. Per VCEP, one [likely] pathogenic residue change at the same codon qualifies for PM5 at moderate strength. The PM5 pipeline did not collect proband counts to support PM5_Strong (≥2 different LP/P residue changes at same codon observed in ≥5 probands), though multiple Q61 variants are established as pathogenic in the literature.	cspec clinvar
PM6	Not met	No de novo observation data available for NM_002524.5:c.183A>C. Per VCEP, PM6 uses point-based scoring (0.5-2 points) requiring confirmed de novo status. No de novo events were identified in ClinVar submissions or literature.	clinvar
PP1	Not met	No co-segregation data available for NM_002524.5:c.183A>C. Per VCEP, PP1 requires ≥3 informative meioses for supporting, ≥5 for moderate, and ≥7 for strong. No family studies were identified.
PP2	N/A	VCEP RASopathy specifications mark PP2 as not applicable because the missense z-score for NRAS is <3.09 in gnomAD.	cspec
PP3	Met	REVEL score for NM_002524.5:c.183A>C (p.Q61H) is 0.742, which meets the VCEP threshold of REVEL ≥ 0.7 for PP3 at supporting strength. SpliceAI predicts no significant splice impact (max delta score = 0.00), consistent with a missense effect predicted to be deleterious.	revel spliceai cspec
PP4	N/A	VCEP RASopathy specifications mark PP4 as not applicable; phenotype specificity is addressed under PS4 instead.	cspec
PP5	N/A	VCEP specifications mark PP5 as not applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	NM_002524.5:c.183A>C is absent from gnomAD (allele frequency = 0). The VCEP BA1 threshold is gnomAD filtering allele frequency ≥ 0.05%. This variant does not meet the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	NM_002524.5:c.183A>C is absent from gnomAD (allele frequency = 0). The VCEP BS1 threshold is gnomAD filtering allele frequency ≥ 0.025%. This variant does not meet the BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	No observations of NM_002524.5:c.183A>C in healthy adult individuals. Variant is absent from gnomAD, which precludes evidence of presence in unaffected controls. Per VCEP point-based scoring, no points can be assigned for BS2.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS3	N/A	VCEP RASopathy specifications mark BS3 as not applicable.	cspec
BS4	Not met	No segregation data demonstrating lack of co-segregation with a RASopathy phenotype. Per VCEP, BS4 requires only one informative meiosis showing non-segregation. No family studies were identified.
BP1	N/A	VCEP BP1 applies only to truncating variants (nonsense, frameshift, canonical splice site, initiation codon, entire gene or multi-exon deletion) in genes where disease mechanism is gain-of-function. NM_002524.5:c.183A>C is a missense substitution, not a truncating variant.	cspec
BP2	Not met	No evidence of an alternative molecular cause of a RASopathy in the same gene, and no cis/trans phase data available. Per VCEP, BP2 requires point-based scoring for an alternative molecular cause. No data meet any point threshold.
BP4	Not met	REVEL score for NM_002524.5:c.183A>C is 0.742, which exceeds the VCEP BP4 threshold of REVEL ≤ 0.3. The in silico prediction does not support a benign interpretation.	revel cspec spliceai
BP5	Not met	No evidence of an alternative molecular cause for a RASopathy in a different gene. Per VCEP, BP5 requires point-based scoring for alternative molecular causes. No data available.
BP6	N/A	VCEP specifications mark BP6 as not applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	VCEP BP7 applies only to synonymous (silent) variants or intronic positions outside canonical splice sites, in conjunction with BP4. NM_002524.5:c.183A>C is a missense substitution producing p.Gln61His and does not qualify.	cspec

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