Variant classification summary

NM_002524.5:c.38G>T

NRAS · NP_002515.1:p.(Gly13Val) · NM_002524.5

GRCh37: chr1:115258744 C>A · GRCh38: chr1:114716123 C>A

Gene: NRAS Transcript: NM_002524.5

Final call

VUS

PM1 moderate PP2 supporting PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.5

Protein

NP_002515.1:p.(Gly13Val)

gnomAD AF

6.195687058324959e-07 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

c.38G>T (p.Gly13Val) is located in the P-loop domain (residues 10-17), an approved functional domain critical for GTP binding and hydrolysis in NRAS, satisfying PM1 at moderate strength per the ClinGen RASopathy VCEP.

2

PP2 is met at supporting strength as this is a missense variant in NRAS, a RASopathy gene where missense variants are a common mechanism of disease, per the VCEP specification.

3

Multiple in silico tools predict a deleterious effect (REVEL = 0.789, BayesDel = 0.314), satisfying PP3 at supporting strength per the VCEP.

4

The variant is present at extremely low frequency in gnomAD (v2.1: 1/251,492; v4.1: 1/1,614,026) and is absent from gnomAD-Canada, consistent with a rare disease-causing variant, though PM2 is not met per strict VCEP requirement for complete absence.

5

The variant has been reported in ClinVar as Likely pathogenic by two clinical laboratories (ClinVar ID 375876) and is annotated as Likely Oncogenic by OncoKB with 141 somatic occurrences in COSMIC, supporting its functional significance, though these alone do not independently meet PS4 or PS5 criteria per VCEP rules.

6

PVS1, PP5, BP6, PP4 are not applicable per the RASopathy VCEP specification. BP1 is not applicable as this is a missense variant, not a truncating variant. BP7 is not applicable as this is not a synonymous variant.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant 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	The ClinGen RASopathy VCEP explicitly designates PVS1 as not applicable for RASopathy genes including NRAS, because loss of function and/or haploinsufficiency have not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype. This is a missense variant (p.Gly13Val), further precluding PVS1 application.	cspec
PS1	Not met	PS1 requires the same amino acid change (p.Gly13Val) to have been previously established as pathogenic per VCEP criteria via a different nucleotide change. No evidence was found that another nucleotide change producing p.Gly13Val in NRAS (e.g., c.38G>A) has been classified as pathogenic in the germline RASopathy context. While the VCEP permits application across analogous residues in Group 1 genes (HRAS, NRAS, KRAS), and G13V in HRAS is a known Costello syndrome variant, insufficient VCEP-level evidence was present in the case materials to confirm this.	cspec clinvar
PS2	Not assessed	PS2 requires a confirmed de novo occurrence (paternity confirmed) in a patient with RASopathy and no family history. No de novo data for NM_002524.5:c.38G>T was identified in the case materials.
PS3	Not met	The RASopathy VCEP requires approved functional studies supporting a damaging effect at Strong strength. The VCEP-approved functional assays for NRAS (RAS activation: PMIDs 19966803, 28594414, 21263000; MEK activation: same PMIDs; ERK activation: 19966803, 28594414) are validated at PS3_Supporting level with control variants G12V, I24N, T58I, and G60E. The p.Gly13Val variant was not directly tested in any of the approved functional study publications. While Gly13 is adjacent to the validated Gly12 residue in the P-loop, the VCEP PS3 criterion only permits Strong strength and the variant falls outside the set of directly validated controls. Domain-level inference from adjacent residue testing does not meet PS3 criteria.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	PS4 requires counting independent proband occurrences. The variant is present in ClinVar as Likely pathogenic from 2 clinical laboratories and is reported in COSMIC with 141 somatic occurrences. However, specific germline proband count data with adjudicable phenotype was not available in the case materials. PMID 19775298 (De Filippi 2009) describes a germline NRAS mutation in a JMML patient, but full text was unavailable to confirm proband details.	clinvar oncokb
PS5	N/A	Designated Not Applicable by the ClinGen RASopathy VCEP. This criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.	cspec
PM1	Met	Gly13 in NRAS lies within the P-loop domain (residues 10-17 in HRAS, analogous in NRAS), which is an approved functional domain in the RASopathy VCEP supplemental material (Alignment with PM1 domains). This is also a statistically significant mutational hotspot per cancerhotspots.org. The VCEP specifies moderate strength for PM1 application at approved functional domains. The P-loop is critical for nucleotide binding and GTPase activity.	cspec vcep_alignment_with_pm1_domains_pptx oncokb
PM2	Not met	The RASopathy VCEP requires complete absence from all population databases. This variant is present in gnomAD v2.1 at 1/251,492 alleles (AF = 3.98 × 10⁻⁶) and in gnomAD v4.1 at 1/1,614,026 alleles (AF = 6.20 × 10⁻⁷). Although extremely rare, the variant is not completely absent, and the VCEP threshold for PM2 is not satisfied.	gnomad_v2 gnomad_v4
PM5	Not assessed	The RASopathy VCEP PM5 rule states it should not be used as an independent criterion in conjunction with PM1 when the residue is a designated mutational hot-spot. Since Gly13 is in the PM1-approved P-loop domain and PM1 is met at moderate, PM5 cannot be independently applied per VCEP rules to avoid premature designation of likely pathogenic classification in the absence of other evidence.	cspec
PM6	Not assessed	PM6 requires a confirmed de novo observation without confirmation of paternity and maternity. No de novo data for NM_002524.5:c.38G>T was identified in the case materials. PMID 19775298 may describe a germline case, but full text was unavailable for verification.
PP1	Not assessed	PP1 requires co-segregation data with at least three informative meioses per VCEP (supporting level). No segregation data was available in the case materials.
PP2	Met	The RASopathy VCEP states that PP2 is applicable to all RASopathy genes described and curated. NRAS is a RASopathy gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. This is a missense variant (p.Gly13Val).	cspec
PP3	Met	Multiple lines of computational evidence support a deleterious effect. REVEL score of 0.789 predicts damaging. BayesDel score of 0.314 supports a deleterious effect. SpliceAI delta score of 0.00 indicates no splicing impact. The VCEP specifies supporting strength for PP3 when multiple lines of computational evidence support a deleterious effect.	revel bayesdel spliceai
PP4	N/A	Designated Not Applicable by the ClinGen RASopathy VCEP. The VCEP states this criterion is not applicable to the RASopathies; see PS4 criterion for proband counting options.	cspec
PP5	N/A	Designated Not Applicable by the ClinGen RASopathy VCEP. This criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.	cspec
BA1	Not met	The RASopathy VCEP sets the BA1 threshold at allele frequency ≥0.05%. This variant has an allele frequency of 3.98 × 10⁻⁶ (0.0004%) in gnomAD v2.1 and 6.20 × 10⁻⁷ (0.00006%) in gnomAD v4.1, well below the VCEP threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The RASopathy VCEP sets the BS1 threshold at allele frequency ≥0.025%. This variant has an allele frequency of 3.98 × 10⁻⁶ (0.0004%) in gnomAD v2.1 and 6.20 × 10⁻⁷ (0.00006%) in gnomAD v4.1, well below the VCEP threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	The RASopathy VCEP states that general population data should not be used for BS2 due to variable expressivity and severity of RASopathies. Clinical laboratories are encouraged to accumulate more than 3 instances of well-phenotyped family members before applying this criterion. No such data was available in the case materials.	cspec
BS3	Not met	BS3 requires approved functional studies showing no damaging effect on protein function. The VCEP-approved functional studies for NRAS are the same assays approved for PS3 (RAS, MEK, ERK activation). No functional data showing a benign effect for p.Gly13Val was identified. The variant was not directly tested in the approved functional studies, and no published data demonstrates a neutral functional effect.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	The RASopathy VCEP requires only one informative meiosis to apply BS4 at strong strength. No segregation data was available in the case materials.
BP1	N/A	The RASopathy VCEP specifies BP1 for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, entire gene or multi-exon deletion) in genes without established LOF correlation to disease. This is a missense variant (p.Gly13Val), not a truncating variant. BP1 is not applicable.	cspec
BP2	Not assessed	BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No such data was available in the case materials.
BP3	N/A	This is a single-nucleotide substitution, not an in-frame deletion/insertion in a repetitive region.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL (0.789) and BayesDel (0.314) both predict a deleterious effect, contradicting BP4. In silico evidence supports pathogenicity (PP3) rather than benign impact.	revel bayesdel spliceai
BP5	Not assessed	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data was available in the case materials.
BP6	N/A	Designated Not Applicable by the ClinGen RASopathy VCEP. This criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.	cspec
BP7	N/A	BP7 is for synonymous (silent) variants with no predicted splice impact. This is a missense variant (p.Gly13Val), not a synonymous variant.

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