About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.183A>T, p.(Gln61His)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PM1Moderate
PM1 · moderate
Residue Q61 is located within the Switch II functional domain (HRAS 57-64), which is explicitly listed as an approved PM1 functional domain in the RASopathy VCEP supplemental material (Alignment-with-PM1-domains). Q61 is also a statistically significant missense hotspot at cancerhotspots.org. NRAS is in the VCEP Group 1 analogous genes (HRAS, NRAS, KRAS).
PM2Moderate
PM2 · moderate
This variant is completely absent from all population databases surveyed (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.
PM5Moderate
PM5 · moderate
Multiple different pathogenic missense changes at NRAS codon Q61 are established in the RASopathy spectrum (e.g., Q61R, Q61K, Q61L in HRAS/KRAS/NRAS). These are well-characterized gain-of-function pathogenic variants at the same residue. Q61H (His) is a non-conservative substitution concordant with the pathogenic direction of other Q61 missense changes. The VCEP mutual-exclusion rule (PM5 not to be used with PM1 when residue is a designated hotspot) does not apply here because Q61 is not individually designated as a mutational hotspot in the PM1 supplemental material — only the Switch II domain (57-64) is listed.
PP2Supporting
PP2 · supporting
PP2 is explicitly applicable to all RASopathy genes described and curated by the VCEP, including NRAS. This is a missense variant in a gene where missense variants are a common mechanism of disease (gain-of-function), with a low rate of benign missense variation at critical residues.
PP3Supporting
PP3 · supporting
Multiple lines of computational evidence support a deleterious effect. REVEL score 0.742 predicts damaging. Residue Q61 is a statistically significant cancer hotspot (cancerhotspots.org). COSMIC reports 168 somatic occurrences at this position. OncoKB classifies as Oncogenic. SpliceAI max delta 0.00 indicates no cryptic splice impact. BayesDel 0.130 is discordant but REVEL and hotspot evidence together provide multiple independent lines of computational support.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
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, PM5 moderate, PP2 supporting, PP3 supporting; combination = 3 moderate + 2 supporting, which maps to Likely Pathogenic.
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.
ClinVar submissions
2 reported laboratory submissions
1 Pathogenic · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
168 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54736991, n = 168 times).
Cancer Hotspots
This variant lies 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: 5 met · 5 not met · 9 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.183A>T (p.Gln61His) in NRAS is a missense variant in the Switch II functional domain (HRAS 57-64), a critical GTPase region where pathogenic gain-of-function variants are well-established in the RASopathy spectrum.
This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the RASopathy VCEP requirement for PM2 at moderate strength.
Multiple different pathogenic missense variants at NRAS codon Q61 (Q61R, Q61K, Q61L) are established in the RASopathy spectrum, supporting PM5 at moderate strength.
PP2 is applicable to all RASopathy genes per VCEP specification, reflecting the low rate of benign missense variation in these genes.
REVEL predicts a damaging effect (score 0.742), and Q61 is a statistically significant cancer hotspot (cancerhotspots.org), supporting PP3 at supporting strength.
This variant has been reported in ClinVar with conflicting classifications: Pathogenic (1 submitter, GeneDx) and Uncertain significance (1 submitter, Hospital for Sick Children). No expert panel review is available.
NRAS Q61H is a well-established somatic oncogenic mutation reported 168 times in COSMIC and classified as Oncogenic (gain-of-function) by OncoKB. Functional studies per the VCEP-approved assay framework exist for NRAS but were not directly verified for this variant in the case materials.
No criteria match.
Met · 5
PM1 ModerateResidue Q61 is located within the Switch II functional domain (HRAS 57-64), which is explicitly listed as an approved PM1 functional domain in the RASopathy VCEP supplemental material (Alignment-with-PM1-domains). Q61 is also a statistically significant missense hotspot at cancerhotspots.org. NRAS is in the VCEP Group 1 analogous genes (HRAS, NRAS, KRAS). Details ▾Hide ▴
Evidence considered
- VCEP PM1 domains: Switch II (HRAS 57-64) includes Q61
- applicable to NRAS via Group 1 analogy. cancerhotspots.org: residue Q61 is a statistically significant hotspot.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM2 ModerateThis variant is completely absent from all population databases surveyed (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
- Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (exomes/genomes). Absent from gnomAD-Canada v1.0.
Sources
PM5 ModerateMultiple different pathogenic missense changes at NRAS codon Q61 are established in the RASopathy spectrum (e.g., Q61R, Q61K, Q61L in HRAS/KRAS/NRAS). These are well-characterized gain-of-function pathogenic variants at the same residue. Q61H (His) is a non-conservative substitution concordant with the pathogenic direction of other Q61 missense changes. The VCEP mutual-exclusion rule (PM5 not to be used with PM1 when residue is a designated hotspot) does not apply here because Q61 is not individually designated as a mutational hotspot in the PM1 supplemental material — only the Switch II domain (57-64) is listed. Details ▾Hide ▴
Evidence considered
- NRAS Q61R
- Q61K
- Q61L are established pathogenic variants at the same residue. Q61H is a non-conservative substitution (Gln→His
- Grantham distance 24) concordant with other oncogenic Q61 changes. Switch II domain listing in PM1 supplemental does not designate individual residues as hotspots
- so PM5/PM1 mutual exclusion does not apply.
Sources
PP2 SupportingPP2 is explicitly applicable to all RASopathy genes described and curated by the VCEP, including NRAS. This is a missense variant in a gene where missense variants are a common mechanism of disease (gain-of-function), with a low rate of benign missense variation at critical residues. Details ▾Hide ▴
Evidence considered
- VCEP RASopathy v1.0: PP2 is applicable to all RASopathy genes curated herein
- including NRAS.
Sources
PP3 SupportingMultiple lines of computational evidence support a deleterious effect. REVEL score 0.742 predicts damaging. Residue Q61 is a statistically significant cancer hotspot (cancerhotspots.org). COSMIC reports 168 somatic occurrences at this position. OncoKB classifies as Oncogenic. SpliceAI max delta 0.00 indicates no cryptic splice impact. BayesDel 0.130 is discordant but REVEL and hotspot evidence together provide multiple independent lines of computational support. Details ▾Hide ▴
Evidence considered
- REVEL 0.742 (pathogenic-leaning). cancerhotspots.org: statistically significant hotspot at Q61. COSMIC: 168 somatic counts. OncoKB: Oncogenic. SpliceAI: no splicing impact (max delta 0.00). BayesDel 0.130 (discordant
- benign-leaning).
Sources
Not met · 5 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change (Q61H) to be previously established as pathogenic per VCEP criteria from a different nucleotide change. No evidence of a different nucleotide change producing NRAS Q61H that has been classified as pathogenic under VCEP in the germline RASopathy context was identified. The ClinVar record for this variant (VCV000373003) has conflicting classifications (Pathogenic/Uncertain significance) with no expert panel review. Details ▾Hide ▴
Evidence considered
- ClinVar VCV000373003: Pathogenic (1 submitter)
- Uncertain significance (1 submitter)
- no expert panel classification. No alternate nucleotide change producing Q61H with established VCEP-level pathogenicity identified.
Still missing
- ClinVar does not contain an expert-panel-level pathogenic classification for NRAS Q61H from an alternate nucleotide change.
Sources
BA1 VCEP BA1 threshold is allele frequency >=0.05%. This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the frequency threshold. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- allele frequency is 0.00%
- which is below the 0.05% VCEP BA1 threshold.
Sources
BS1 VCEP BS1 threshold is allele frequency >=0.025%. This variant is completely absent from all population databases surveyed. Does not meet the frequency threshold. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- allele frequency is 0.00%
- which is below the 0.025% VCEP BS1 threshold.
Sources
BS3 BS3 requires approved functional studies showing no damaging effect on protein function. NRAS Q61H is a well-established gain-of-function mutation (OncoKB: Oncogenic). All available evidence points toward a damaging gain-of-function effect, not a benign or normal functional outcome. Details ▾Hide ▴
Evidence considered
- OncoKB: Oncogenic
- gain-of-function. COSMIC: 168 somatic counts. cancerhotspots.org: significant hotspot. No evidence of normal protein function for this variant.
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score 0.742 predicts a damaging effect. The variant is a statistically significant cancer hotspot. BayesDel 0.130 is low but does not outweigh the multiple lines of evidence supporting a deleterious effect (REVEL, hotspot status, COSMIC prevalence, OncoKB oncogenic classification). Multiple independent lines do not uniformly suggest no impact. Details ▾Hide ▴
Evidence considered
- REVEL 0.742 (damaging). BayesDel 0.130 (benign-leaning). SpliceAI 0.00 (no splicing impact). cancerhotspots.org: significant hotspot. OncoKB: Oncogenic. Evidence is mixed
- with multiple pathogenic-leaning signals.
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo occurrence report for NM_002524.5:c.183A>T (NRAS Q61H) with confirmed paternity in a RASopathy patient was identified in the case materials or literature reviewed. Details ▾Hide ▴
Still missing
- No de novo data available in case materials. Proband phenotype and family history not provided.
PS3 The RASopathy VCEP has approved functional assays for NRAS (RAS Activation, MEK Activation, ERK Activation; PMIDs 19966803, 28594414, 21263000) at PS3_Supporting strength per assay. However, the approved functional study papers are not present in the case materials and could not be directly verified for variant-specific testing of NRAS Q61H. OncoKB classifies this variant as Oncogenic (gain-of-function), and NRAS Q61H is a well-established activating mutation. Cannot independently confirm variant-specific functional data from approved VCEP studies. Details ▾Hide ▴
Evidence considered
- VCEP-approved functional assays exist for NRAS (RAS/MEK/ERK activation). OncoKB: Oncogenic
- gain-of-function. COSMIC: 168 somatic occurrences. cancerhotspots.org: statistically significant hotspot at Q61.
Still missing
- Approved VCEP functional study papers (19966803
- 28594414
- 21263000) not available in case folder for direct variant-specific verification.
Sources
PS4 No independent RASopathy-affected proband counts are available in the case materials. The ClinVar record (VCV000373003) has 2 clinical submissions but no proband-level phenotype data. PS4 under VCEP requires independent occurrence counts (>=1 for Supporting, >=3 for Moderate, >=5 for Strong) in patients with RASopathy phenotype. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 clinical laboratory submissions (1 Pathogenic
- 1 Uncertain significance). No proband-level RASopathy phenotype data available.
Still missing
- No RASopathy-affected proband counts or case-control data available.
Sources
PM6 No de novo occurrence report (with or without confirmed parentage) was identified in the case materials or reviewed literature for this variant in a RASopathy patient. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No co-segregation data or family studies are available in the case materials for this variant. PP1 under VCEP requires at least 3 informative meioses at the Supporting level. Details ▾Hide ▴
Still missing
- No segregation or family data available.
BS2 VCEP restricts BS2: due to variable expressivity and severity of RASopathies, general population data should not be used. Requires more than 3 instances of well-phenotyped family members. No such data is available in the case materials. Details ▾Hide ▴
Evidence considered
- VCEP restricts BS2 to well-phenotyped family members
- no such data available.
Still missing
- No well-phenotyped healthy adult carrier data available.
BS4 No segregation data (supporting or refuting co-segregation) is available in the case materials. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No data on whether this variant has been observed in trans with a pathogenic variant (for a dominant disorder) or in cis with a pathogenic variant is available in the case materials. Details ▾Hide ▴
Still missing
- No cis/trans phase data available.
BP5 No evidence of an alternate molecular basis for disease in a patient carrying this variant was identified in the case materials. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable per RASopathy VCEP: LOF and/or haploinsufficiency has not been clearly identified as a disease mechanism for NRAS relative to the RASopathy spectrum phenotype. This is also a missense variant, not a null variant. Details ▾Hide ▴
Evidence considered
- VCEP RASopathy v1.0 explicitly designates PVS1 as Not Applicable for NRAS.
Sources
PM3 VCEPSkipped — PM3 applies to recessive disorders (detected in trans with a pathogenic variant). RASopathies are dominant disorders. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped — PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPNot applicable per RASopathy VCEP: PP4 is designated as Not Applicable for this VCEP. Details ▾Hide ▴
PP5 VCEPNot applicable per RASopathy VCEP: PP5 is designated as Not Applicable — 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
BP1 N/AVCEP BP1 applies to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, single/multi-exon deletion) in genes without established LOF correlation to disease. NM_002524.5:c.183A>T is a missense variant (p.Gln61His), not a truncating variant. Details ▾Hide ▴
Evidence considered
- VCEP BP1 is for truncating variants only
- this is a missense substitution.
Sources
BP3 N/ASkipped — BP3 applies to in-frame deletions/insertions in repetitive regions. This is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPNot applicable per RASopathy VCEP: BP6 is designated as Not Applicable — 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_002524.5:c.183A>T is a missense variant (p.Gln61His), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- BP7 is for synonymous variants only
- this is a missense substitution.
Sources
PS5 N/APS5 is not defined in the ClinGen RASopathy VCEP criteria specification (version 1.0). This criterion is not part of the VCEP framework for NRAS. Details ▾Hide ▴
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.5
- Coding (HGVS c.)
- NM_002524.5:c.183A>T
- Protein (HGVS p.)
- NP_002515.1:p.(Gln61His)
- GRCh38
- chr1:114713907 T>A
- GRCh37
- chr1:115256528 T>A
- ClinVar
- 373003
- COSMIC
- COSV54736991
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
- 0.742
- BayesDel
- 0.130
How the predictions were used
PP3 SupportingMultiple lines of computational evidence support a deleterious effect. REVEL score 0.742 predicts damaging. Residue Q61 is a statistically significant cancer hotspot (cancerhotspots.org). COSMIC reports 168 somatic occurrences at this position. OncoKB classifies as Oncogenic. SpliceAI max delta 0.00 indicates no cryptic splice impact. BayesDel 0.130 is discordant but REVEL and hotspot evidence together provide multiple independent lines of computational support. Details ▾Hide ▴
Evidence considered
- REVEL 0.742 (pathogenic-leaning). cancerhotspots.org: statistically significant hotspot at Q61. COSMIC: 168 somatic counts. OncoKB: Oncogenic. SpliceAI: no splicing impact (max delta 0.00). BayesDel 0.130 (discordant
- benign-leaning).
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score 0.742 predicts a damaging effect. The variant is a statistically significant cancer hotspot. BayesDel 0.130 is low but does not outweigh the multiple lines of evidence supporting a deleterious effect (REVEL, hotspot status, COSMIC prevalence, OncoKB oncogenic classification). Multiple independent lines do not uniformly suggest no impact. Details ▾Hide ▴
Evidence considered
- REVEL 0.742 (damaging). BayesDel 0.130 (benign-leaning). SpliceAI 0.00 (no splicing impact). cancerhotspots.org: significant hotspot. OncoKB: Oncogenic. Evidence is mixed
- with multiple pathogenic-leaning signals.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_002524.5:c.183A>T is a missense variant (p.Gln61His), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- BP7 is for synonymous variants only
- this is a missense substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.742. BayesDel score = 0.13014.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
-
PMID 23103856 ↗Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling.Young A et al. · 2013NRAS Q61H is explicitly identified as the oncogenic driver in the RD rhabdomyosarcoma cell line. The study demonstrates that oncogenic N-Ras Q61H regulates basal MAPK signaling and negatively regulates EGFR sensitivity, while wild-type Ras isoforms mediate growth factor-induced signaling. Both oncogenic and wild-type Ras are required for optimal proliferation of NRAS Q61H-mutant cells.Names this variant
Quoted passage
the RD rhabdomyosarcoma cell line (NRAS Q61H; Catalog of Somatic Mutations in Cancer, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom)
Introduction, paragraph 3; Results, Figure 1; Figure 2
-
PMID 10574788 ↗The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins.Structural study of the pre-hydrolysis state of p21(ras) in complex with GTP. Investigates the role of water molecules in the GTP hydrolysis reaction of Ras-like proteins. Does not specifically mention NRAS Q61H or any specific disease-associated variant.Does not name this variant
-
PMID 20194776 ↗Allosteric modulation of Ras positions Q61 for a direct role in catalysis.Structural biology study of H-Ras investigating the catalytic role of Q61 in GTP hydrolysis. Demonstrates that Q61 is positioned in the active site through an allosteric switch involving helix 3/loop 7 and is critical for intrinsic GTP hydrolysis. Mutants of residue Q61 impair GTPase activity and are found prominently in human cancers. The study uses H-Ras, not NRAS, and does not specifically test or mention NRAS Q61H.Does not name this variant
Quoted passage
Mutants of residue Q61 impair the GTPase activity of Ras and are found prominently in human cancers.
Abstract; Introduction; Results; Discussion
-
PMID 25148578 ↗Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma.Clinical NGS panel testing study of 699 advanced melanoma patients. Reports that NRAS mutations affecting Q61 were the most prevalent (77% of all NRAS mutations) in this melanoma cohort. The study does not enumerate individual Q61 substitutions and does not specifically identify NRAS Q61H as a distinct variant among the Q61-mutant cases.Does not name this variant
Quoted passage
For NRAS, mutations affecting Q61 were the most prevalent (77% of all NRAS mutations), followed by G12/13 (20%).
Results section (NRAS mutation prevalence); Figure S3c
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PMID 26090869 ↗Molecular spectrum of BRAF, NRAS and KRAS gene mutations in plasma cell dyscrasias: implication for MEK-ERK pathway activation.Targeted NGS study of BRAF, NRAS, and KRAS mutations in 167 patients with plasma cell dyscrasias (multiple myeloma, primary and secondary plasma cell leukemia). NRAS Q61H was identified in multiple myeloma patients at varying variant allele fractions. In sequential samples, NRAS Q61H was observed to persist at stable VAF or emerge during disease progression, supporting its role as a driver mutation in multiple myeloma.Names this variant
Quoted passage
the loss of KRAS G12V in MM-146, which showed a concurrent increase in the allele frequency of NRAS Q61H from 8% to 41%
Results (NRAS and KRAS mutations); Table 2; Figure 4
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is the foundational reference for the variant classification framework and does not discuss any specific variant, including NM_002524.5:c.183A>T.Does not name this variant
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PMID 35101336 ↗Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).Horak P et al. · 2022Joint consensus recommendations for classification of somatic variant oncogenicity by ClinGen, CGC, and VICC. This guideline addresses somatic cancer variant interpretation and does not discuss any specific germline variant, including NM_002524.5:c.183A>T.Does not name this variant
-
PMID 23619274 ↗American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.Cooley LD et al. · 2013ACMG technical standards and guidelines for microarray analysis in neoplastic disorders. Does not discuss NRAS or germline variants.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
1 Pathogenic · 1 Uncertain significance
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/373003/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115256528-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114713907-T-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-114713907-T-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.5%3Ac.183A…
- OncoKB ↗www.oncokb.org/gene/NRAS/Q61H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136034274
- 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 as Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 373003)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.742. BayesDel score = 0.13014.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54736991, n = 168 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.