NM_002524.4:c.173C>T

NRAS · NP_002515.1:p.(Thr58Ile) · NM_002524.4

GRCh37: chr1:115256538 G>A · GRCh38: chr1:114713917 G>A

Gene: NRAS Transcript: NM_002524.4

Final call

VUS

PS3 moderate PM1 moderate PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.4

Protein

NP_002515.1:p.(Thr58Ile)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The NRAS NM_002524.4:c.173C>T (NP_002515.1:p.Thr58Ile; NP_002515.1:p.T58I) variant has been observed in somatic cancers in COSMIC (COSV54738937, n=4) and has been reported in ClinVar as pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

In the RASopathy VCEP-approved functional studies resource, NRAS p.Thr58Ile is listed as a pathogenic or likely pathogenic validation control across multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays, supporting an abnormal activating effect.

Computational evidence supports a damaging missense effect, with REVEL 0.959 and BayesDel 0.45829, while SpliceAI predicts no significant splice impact (maximum delta score 0.01).

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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 is a missense variant, and the NRAS RASopathy VCEP framework lists PVS1 as not applicable. The generic PVS1 scaffold also does not apply because this variant is not a nonsense, frameshift, or canonical +/-1,2 splice variant.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant causing the same amino acid change from a different nucleotide change was identified in the available evidence.	clinvar cspec
PS2	Not assessed	This variant has been reported in germline disease databases, but no confirmed de novo occurrence with both maternity and paternity established was identified in the available evidence.	clinvar cspec
PS3	Met	In the RASopathy VCEP-approved functional studies resource, NRAS p.Thr58Ile is listed among pathogenic or likely pathogenic validation controls in multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays. These data support an abnormal functional effect consistent with pathogenic activation.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Not assessed	This variant has been observed in affected submissions in ClinVar, but the available evidence does not provide the proband counts or point-based case evidence needed for PS4 under the NRAS RASopathy VCEP framework.	clinvar cspec
PM1	Met	The p.Thr58Ile change lies in the NRAS Switch II region (amino acids 57-64), which the NRAS RASopathy VCEP designates as a critical and well-established functional domain for PM1.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the NRAS RASopathy VCEP PM2 requirement that the variant be absent from controls.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the NRAS RASopathy VCEP framework.	cspec
PM4	N/A	This variant is a missense substitution and does not cause a protein length change, in-frame deletion, or in-frame insertion, so PM4 does not apply.	cspec
PM5	Not met	No different pathogenic or likely pathogenic missense change at the same codon was identified in the available evidence to support PM5.	clinvar cspec
PM6	Not assessed	No assumed de novo occurrence without confirmed maternity and paternity was documented in the available evidence, so PM6 was not applied.	clinvar cspec
PP1	Not assessed	No segregation data were identified to support or refute cosegregation with disease.	cspec
PP2	N/A	PP2 is not applicable in the NRAS RASopathy VCEP framework.	cspec
PP3	Met	For this missense variant, the REVEL score is 0.959, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7. BayesDel is also positive at 0.45829, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, supporting a missense rather than splice-driven damaging effect.	revel bayesdel spliceai cspec
PP4	N/A	PP4 is not applicable in the NRAS RASopathy VCEP framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD and therefore is below the BA1 stand-alone benign threshold of 0.05%.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD and therefore is below the BS1 strong benign threshold of 0.025%.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No observations in clearly unaffected individuals were identified to support BS2.	cspec
BS3	N/A	BS3 is not applicable in the NRAS RASopathy VCEP framework for this evidence set, and no validated benign functional evidence was identified.	cspec
BS4	Not assessed	No nonsegregation data were identified to support BS4.	cspec
BP1	N/A	BP1 in this framework is intended for truncating or loss-of-function variants in a gain-of-function RASopathy gene. This variant is missense, so BP1 does not apply.	cspec
BP2	Not assessed	No evidence was identified that this variant was observed with an alternative molecular explanation meeting the VCEP BP2 point-based framework.	cspec
BP3	N/A	BP3 is not applicable in the NRAS RASopathy VCEP framework.	cspec
BP4	Not met	Computational evidence does not support a benign interpretation. The REVEL score is 0.959, which is above the BP4 benign threshold of 0.3, and BayesDel is also positive at 0.45829. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, but that does not outweigh the damaging missense predictions.	revel bayesdel spliceai cspec
BP5	Not assessed	No alternative molecular cause explaining the phenotype was identified to support BP5.	cspec
BP6	N/A	BP6 is not applicable in the NRAS RASopathy VCEP framework.	cspec
BP7	N/A	This variant is missense rather than synonymous or intronic, so BP7 does not apply.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.