About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.101C>T, p.(Pro34Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen NRAS VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
Residue Pro34 is located within the Switch I domain of NRAS (analogous to HRAS aa 25-40), which is a VCEP-approved critical functional domain per the supplemental material (Alignment-with-PM1-domains.pptx). Switch I is essential for GTP binding and effector interactions in RAS proteins. The VCEP explicitly permits PM1 application across analogous residues in Group 1 genes (HRAS, NRAS, KRAS). The variant substitutes proline with leucine, altering a residue within this well-established functional domain.
PM2Moderate
PM2 · moderate
NM_002524.5:c.101C>T is completely absent from all population databases queried (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0), satisfying the RASopathy VCEP requirement that the variant must be completely absent from all population databases.
PP2Supporting
PP2 · supporting
The RASopathy VCEP explicitly states that PP2 is applicable to all RASopathy genes described and curated in its scope, including NRAS. This is a missense variant in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PP2 supporting; combination = 2 moderate + 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: no assertion criteria provided.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NRAS, a GTPase, is mutated in a diverse range of cancers, most frequently in melanoma and thyroid cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54738538, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen NRAS VCEP v1.0, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 16 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002524.5:c.101C>T (p.Pro34Leu) in NRAS is a missense variant located in the Switch I functional domain, a VCEP-approved critical domain per the RASopathy Expert Panel supplemental material.
This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying the RASopathy VCEP PM2 requirement of complete absence from all population databases.
PP2 applies by VCEP rule, as missense variants in RASopathy genes have a low rate of benign missense variation.
PVS1, PP4, PP5, and BP6 are not applicable per explicit RASopathy VCEP specification.
No PS3 functional data from VCEP-approved assays are available for this specific variant; OncoKB reports Unknown Oncogenic Effect. The somatic observation in keratinocytic epidermal nevi (PMID:22499344) does not meet VCEP functional study requirements.
No germline RASopathy probands, de novo events, or segregation data have been identified for this variant in the literature reviewed; PS4, PS2, PM6, and PP1 are not met.
REVEL score of 0.845 supports a deleterious effect, but BayesDel (0.347) and SpliceAI (0.00) do not provide additional independent lines, so PP3 is not met.
Applying the generic ACMG/AMP 2015 classification framework (PMID:25741868) as a fallback due to the absence of RASopathy VCEP-specific final combination rules: two moderate criteria (PM1, PM2) and one supporting criterion (PP2) do not reach the threshold for Likely Pathogenic classification (requires e.g., 3 moderate, or 2 moderate + 2 supporting, or 1 strong + 1-2 moderate). This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM1 ModerateResidue Pro34 is located within the Switch I domain of NRAS (analogous to HRAS aa 25-40), which is a VCEP-approved critical functional domain per the supplemental material (Alignment-with-PM1-domains.pptx). Switch I is essential for GTP binding and effector interactions in RAS proteins. The VCEP explicitly permits PM1 application across analogous residues in Group 1 genes (HRAS, NRAS, KRAS). The variant substitutes proline with leucine, altering a residue within this well-established functional domain. Details ▾Hide ▴
Evidence considered
- Switch I domain (HRAS 25-40
- analogous to NRAS) is a VCEP-approved critical functional domain.
- NRAS P34 is within Switch I.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM2 ModerateNM_002524.5:c.101C>T is completely absent from all population databases queried (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0), satisfying the RASopathy VCEP requirement that the variant must be completely absent from all population databases. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1
- gnomAD v4.1
- and gnomAD-Canada v1.0.
Sources
PP2 SupportingThe RASopathy VCEP explicitly states that PP2 is applicable to all RASopathy genes described and curated in its scope, including NRAS. This is a missense variant in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Details ▾Hide ▴
Evidence considered
- VCEP RASopathy Expert Panel v1.0: PP2 is applicable to all RASopathy genes described and curated herein.
Sources
Not met · 16 · evaluated, threshold not reached
PS1 No previously established pathogenic variant resulting in the same amino acid change (p.Pro34Leu) at this residue in NRAS or in analogous Group 1 genes (HRAS, KRAS) has been identified. The somatic NRAS p.P34L observation in keratinocytic epidermal nevi (PMID:22499344) does not constitute a germline pathogenic variant established per RASopathy VCEP criteria. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rule requires a previously established pathogenic germline variant with the same amino acid change
- none identified.
Still missing
- No germline P34L pathogenic variant documented in ClinVar or literature.
Sources
PS2 No de novo occurrence with confirmed paternity identified in the literature reviewed for this case. Details ▾Hide ▴
Still missing
- No de novo reports found.
PS3 The RASopathy VCEP limits PS3 to approved functional studies listed in the supplemental material. The approved assays for NRAS (RAS Activation, MEK Activation, ERK Activation, AKT Phosphorylation) reference PMIDs 19966803, 28594414, and 21263000, none of which are in this case's publication set. The somatic observation of NRAS p.P34L in keratinocytic epidermal nevi (PMID:22499344) confirms this variant can occur as an activating somatic mutation, but this is not a VCEP-approved functional study. OncoKB reports Unknown Oncogenic Effect for this variant. Details ▾Hide ▴
Evidence considered
- VCEP-approved functional study PMIDs (19966803
- 28594414
- 21263000) are not available in the case publication set.
- OncoKB: Unknown Oncogenic Effect.
Still missing
- VCEP-approved functional studies not available for this specific variant.
Sources
PS4 The only report of this variant is in a somatic mosaic context (keratinocytic epidermal nevus, PMID:22499344), which does not meet the VCEP definition of an independent occurrence in a germline RASopathy proband. No germline RASopathy cases with this variant have been documented. Details ▾Hide ▴
Evidence considered
- One somatic observation of NRAS p.P34L in KEN (PMID:22499344) does not qualify as a germline RASopathy proband.
Still missing
- No germline RASopathy probands with this variant documented.
Sources
PM5 NM_002524.5:c.101C>T (p.Pro34Leu) is a missense variant eligible for PM5 consideration under the VCEP rule, which requires a previously established pathogenic missense variant at the same residue (or analogous residue in Group 1 genes HRAS, NRAS, KRAS). No pathogenic missense variant at NRAS P34 has been identified in ClinVar, literature, or the analogous residues in HRAS/KRAS. The somatic NRAS p.P34L observation in KEN (PMID:22499344) does not establish the residue as harboring a germline pathogenic variant. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variant at NRAS P34 (or analogous HRAS/KRAS residues) identified in ClinVar.
- RASopathy VCEP PM5 rule requires a previously established pathogenic variant at the same residue.
Still missing
- No previously established pathogenic variant at NRAS P34 in germline context.
Sources
PM6 No de novo report for this variant, with or without confirmation of paternity/maternity, was identified in the literature reviewed. Details ▾Hide ▴
Still missing
- No de novo reports identified.
PP1 No segregation data are available for this variant. The RASopathy VCEP requires at least three informative meioses to apply PP1 at any strength. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP3 The RASopathy VCEP requires multiple lines of computational evidence supporting a deleterious effect. REVEL score of 0.845 provides one line supporting pathogenicity, but BayesDel at 0.347 does not reach a clear threshold, and SpliceAI delta is 0.00 (no splice impact). Only one computational tool (REVEL) unambiguously supports a deleterious effect, which does not satisfy the VCEP requirement for multiple independent computational lines. Details ▾Hide ▴
Evidence considered
- REVEL: 0.845 (deleterious).
- BayesDel: 0.347 (borderline
- below typical threshold).
- SpliceAI max delta: 0.00 (no splicing impact).
Still missing
- Only REVEL unambiguously supports deleterious effect
- multiple lines required by VCEP.
Sources
BA1 The variant is absent from all population databases queried, with an allele frequency of 0, well below the RASopathy VCEP BA1 threshold of ≥0.05% (5e-4). Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0
- VCEP BA1 threshold is ≥0.05%.
Sources
BS1 The variant is absent from all population databases queried, well below the RASopathy VCEP BS1 threshold of ≥0.025%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0
- VCEP BS1 threshold is ≥0.025%.
Sources
BS2 The RASopathy VCEP instructs that general population data should not be used for BS2 due to variable expressivity and severity. Clinical laboratories are encouraged to accumulate more than 3 instances of well-phenotyped family members before applying this criterion. No such data are available for this variant. Details ▾Hide ▴
Evidence considered
- VCEP: population data should not be used for BS2
- need >3 well-phenotyped family members.
Still missing
- No well-phenotyped family member data available.
Sources
BS3 No VCEP-approved functional study demonstrates a benign effect for this variant. The approved assays and their associated PMIDs are not available in the case publication set. Details ▾Hide ▴
Evidence considered
- VCEP-approved functional studies not available for benign effect assessment.
Still missing
- No VCEP-approved functional study showing no damaging effect.
Sources
BS4 No segregation data available to assess lack of segregation in affected family members. The RASopathy VCEP requires one informative meiosis. Details ▾Hide ▴
Still missing
- No segregation data.
BP2 No evidence that this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Still missing
- No phase data with pathogenic variants available.
BP4 The RASopathy VCEP requires multiple lines of computational evidence suggesting no impact. REVEL score of 0.845 indicates a deleterious effect, contradicting the requirements for BP4. BayesDel at 0.347 is borderline, and SpliceAI delta is 0.00. The computational evidence does not support a conclusion of no impact. Details ▾Hide ▴
Evidence considered
- REVEL 0.845 suggests damaging effect
- precluding BP4.
Sources
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No cases with alternate molecular basis identified.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPLOF and/or haploinsufficiency has not been clearly identified as a disease mechanism for NRAS relative to the RASopathy spectrum phenotype; the RASopathy VCEP explicitly designates PVS1 as not applicable for this gene. Details ▾Hide ▴
Evidence considered
- VCEP RASopathy Expert Panel v1.0 explicitly lists PVS1 as Not Applicable for this VCEP.
Sources
PM3 VCEPSubstitution variant, and RASopathy VCEP designates PM3 as not applicable for RASopathies. Details ▾Hide ▴
Sources
PM4 N/ASubstitution variant; PM4 applies to in-frame deletions/insertions and stop-loss variants. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPThe RASopathy VCEP explicitly designates PP4 as not applicable for RASopathies, directing use of PS4 for proband counting instead. Details ▾Hide ▴
PP5 VCEPThe RASopathy VCEP explicitly designates PP5 as not for use, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
- VCEP: criterion not for use as recommended by the ClinGen SVI VCEP Review Committee.
Sources
BP1 N/AThe RASopathy VCEP specifies BP1 applies to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene deletions) in genes without established LOF correlation. NRAS p.Pro34Leu is a missense variant, and the RASopathy disease mechanism is gain-of-function, not loss-of-function. Details ▾Hide ▴
Evidence considered
- VCEP: BP1 applies only to truncating variants
- this is a missense variant.
Sources
BP3 N/ASubstitution variant; BP3 applies to in-frame deletions/insertions in repetitive regions. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPThe RASopathy VCEP explicitly designates BP6 as not for use, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
- VCEP: criterion not for use as recommended by the ClinGen SVI VCEP Review Committee.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants. NM_002524.5:c.101C>T is a missense variant (p.Pro34Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- c.101C>T is a missense substitution
- not synonymous.
PS5 N/AThe RASopathy VCEP does not define PS5. PS5 is a very-strong extension of PP5 (reputable source reports variant as pathogenic), and the VCEP explicitly designates PP5 as not for use per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.5
- Coding (HGVS c.)
- NM_002524.5:c.101C>T
- Protein (HGVS p.)
- NP_002515.1:p.(Pro34Leu)
- GRCh38
- chr1:114716060 G>A
- GRCh37
- chr1:115258681 G>A
- ClinVar
- 39647
- COSMIC
- COSV54738538
Gene diagram
Every interpreted variant in NRAS, mapped onto the exon structure of NM_002524.5. Select a row to find it on the plot.
NRASNM_002524.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.845
- BayesDel
- 0.347
How the predictions were used
PP3 The RASopathy VCEP requires multiple lines of computational evidence supporting a deleterious effect. REVEL score of 0.845 provides one line supporting pathogenicity, but BayesDel at 0.347 does not reach a clear threshold, and SpliceAI delta is 0.00 (no splice impact). Only one computational tool (REVEL) unambiguously supports a deleterious effect, which does not satisfy the VCEP requirement for multiple independent computational lines. Details ▾Hide ▴
Evidence considered
- REVEL: 0.845 (deleterious).
- BayesDel: 0.347 (borderline
- below typical threshold).
- SpliceAI max delta: 0.00 (no splicing impact).
Still missing
- Only REVEL unambiguously supports deleterious effect
- multiple lines required by VCEP.
Sources
BP4 The RASopathy VCEP requires multiple lines of computational evidence suggesting no impact. REVEL score of 0.845 indicates a deleterious effect, contradicting the requirements for BP4. BayesDel at 0.347 is borderline, and SpliceAI delta is 0.00. The computational evidence does not support a conclusion of no impact. Details ▾Hide ▴
Evidence considered
- REVEL 0.845 suggests damaging effect
- precluding BP4.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants. NM_002524.5:c.101C>T is a missense variant (p.Pro34Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- c.101C>T is a missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.845. BayesDel score = 0.347316.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
-
PMID 20876176 ↗Noonan syndrome: clinical features, diagnosis, and management guidelines.Romano AA et al. · 2010Clinical management guidelines for Noonan syndrome, providing a general review of NS features, genetic causes, and diagnostic approaches. NRAS is mentioned among the RAS/MAPK pathway genes implicated in NS, but the specific variant NM_002524.5:c.101C>T (p.Pro34Leu) is not discussed or reported.Does not name this variant
-
PMID 20963938 ↗CEBPA-Associated Familial Acute Myeloid Leukemia (AML).Adam MP et al. · 1993GeneReview on CEBPA-associated familial acute myeloid leukemia. This paper concerns the CEBPA gene, not NRAS. The variant NM_002524.5:c.101C>T (p.Pro34Leu) was not identified.Does not name this variant
-
PMID 22499344 ↗Keratinocytic epidermal nevi are associated with mosaic RAS mutations.Hafner C et al. · 2012Identified NRAS p.P34L as one of three NRAS somatic mutations in keratinocytic epidermal nevi (KEN), a benign congenital skin lesion resulting from postzygotic mosaicism. The mutation was detected in one KEN sample by SNaPshot assay, confirming this variant can occur as a somatic activating RAS mutation in a mosaic disorder. No germline RASopathy phenotype was reported in this patient.Names this variant
Quoted passage
Three KEN harboured mutations in NRAS (p.G12D, p.P34L, and p.Q61R) and one in KRAS (p.G12D).
Results, line 196-198: 'Three KEN harboured mutations in NRAS (p.G12D, p.P34L, and p.Q61R).'
-
PMID 23970018 ↗Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Fey MF et al. · 2013ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up of acute myeloblastic leukemia in adult patients. Discusses AML risk stratification by karyotype and molecular genetics (FLT3, NPM1, CEBPA), but does not mention NRAS variants or NM_002524.5:c.101C>T (p.Pro34Leu).Does not name this variant
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PMID 33661592 ↗RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies.Adam MP et al. · 1993GeneReview on RUNX1 familial platelet disorder with associated myeloid malignancies. This paper concerns RUNX1, not NRAS. The variant NM_002524.5:c.101C>T (p.Pro34Leu) was not identified.Does not name this variant
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PMID 25173338 ↗2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Authors/Task Force members et al. · 2014ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Background review paper on HCM; does not discuss NRAS or NM_002524.5:c.101C>T.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637576
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/39647/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115258681-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114716060-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-114716060-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.5%3Ac.101C…
- OncoKB ↗www.oncokb.org/gene/NRAS/P34L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136051820
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 39647)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.845. BayesDel score = 0.347316.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NRAS, a GTPase, is mutated in a diverse range of cancers, most frequently in melanoma and thyroid cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54738538, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.