Variant classification summary

NM_002524.5:c.182A>T

NRAS · NP_002515.1:p.(Gln61Leu) · NM_002524.5

GRCh37: chr1:115256529 T>A · GRCh38: chr1:114713908 T>A

Gene: NRAS Transcript: NM_002524.5

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.5

Protein

NP_002515.1:p.(Gln61Leu)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Moderate): codon 61 lies in the Switch II (residues 57-64) critical functional domain.

2

PM2 (Supporting): the variant is absent from gnomAD v2.1 and v4.1.

3

PP3 (Supporting): REVEL score 0.897 exceeds the >=0.7 threshold.

4

Total: 4 SVI points (VUS range 0-5) under ClinGen RASopathy VCEP v2.3, with no pathogenic or benign rule satisfied, yielding a VUS.

Final determination: No ClinGen RASopathy VCEP NRAS v2.3 combination rule is satisfied by PM1(moderate)+PM2(supporting)+PP3(supporting), so the variant is VUS.

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	Not applicable: this is a missense change (p.Gln61Leu), and loss-of-function is not an established NRAS disease mechanism.	cspec
PS1	Not assessed	Not assessed: no established germline pathogenic classification of Gln61Leu at NRAS codon 61 or an analogous paralog residue was available.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no de novo occurrence with both maternity and paternity confirmed was reported.	cspec
PS3	Not assessed	Not assessed: no quantitative results from an approved functional assay (e.g., RAS/MEK/ERK activation) for this variant were available.
PS4	Not assessed	Not assessed: no germline case series or case-control data for p.Gln61Leu with proband counts was available.	cspec
PM1	Met	Met (Moderate): codon 61 falls within the Switch II (SW2, residues 57-64) critical functional domain.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	Met (Supporting): absent from both gnomAD v2.1 and v4.1 population databases.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PM3 is a recessive criterion, and NRAS-associated RASopathy is autosomal dominant.	cspec
PM4	N/A	Not applicable: this missense change does not alter protein length, which PM4 requires.	cspec
PM5	Not assessed	Not assessed: no established pathogenic or likely pathogenic change at NRAS codon 61 (e.g., Gln61Arg/Lys) was documented.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no affected individual with the variant absent from parents was reported.	cspec
PP1	Not assessed	Not assessed: no family segregation data or informative meioses were available.	cspec
PP2	N/A	Not applicable: the RASopathy VCEP lists PP2 as not applicable for NRAS.	cspec
PP3	Met	Met (Supporting): REVEL score 0.897 exceeds the >=0.7 VCEP threshold for missense variants.	cspec revel
PP4	N/A	Not applicable: the RASopathy VCEP designates PP4 as not applicable for NRAS.	cspec
PP5	N/A	Not applicable: the RASopathy VCEP designates PP5 as not applicable, and no expert-panel ClinVar submission exists.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD, far below the >=0.05% allele frequency threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD, far below the >=0.025% allele frequency threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no observations of the variant in healthy or unaffected individuals were available.	cspec
BS3	N/A	Not applicable: the RASopathy VCEP marks BS3 as not applicable for NRAS.	cspec
BS4	Not assessed	Not assessed: no informative non-segregation observation in an affected family member was available.	cspec
BP1	N/A	Not applicable: BP1 applies to truncating variants, and this is a missense change.	cspec
BP2	Not assessed	Not assessed: no alternate molecular cause or cis/trans phase evidence was available.	cspec
BP3	N/A	Not applicable: this is not an in-frame indel, and the VCEP designates BP3 as not applicable for NRAS.	cspec
BP4	Not met	Not met: REVEL score 0.897 is far above the <=0.3 threshold required for BP4.	cspec revel spliceai
BP5	Not assessed	Not assessed: no documented alternate molecular diagnosis fully explaining the phenotype was available.	cspec
BP6	N/A	Not applicable: the VCEP designates BP6 as not applicable, and no expert-panel benign or likely benign ClinVar assertion exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or non-coding variants, and this is missense.	cspec

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