About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.182A>G, p.(Gln61Arg)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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 v2.3.0. 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: 6
Benign evidence criteria: 0
Pathogenic criteria applied · 6
PS1Strong
PS1 · strong
The p.Gln61Arg (Q61R) amino acid change is an established pathogenic variant at the analogous residue in HRAS and KRAS. The RASopathy VCEP explicitly allows PS1 at Strong strength for the same amino acid change as a previously established pathogenic variant in HRAS, KRAS, MRAS, NRAS, RIT1, or RRAS2.
PS3Moderate
PS3 · moderate
The RASopathy VCEP has approved four functional assay types for NRAS: RAS Activation, MEK Activation, ERK Activation, and AKT Phosphorylation assays. The variant p.Gln61Arg has been characterized in at least two different approved assay platforms across VCEP-vetted publications (PMIDs: 19966803, 28594414, 21263000), satisfying the VCEP PS3 Moderate requirement of two or more unique assay types.
PM1Moderate
PM1 · moderate
The variant p.Gln61Arg (residue 61) lies within the Switch II (SW2) domain (amino acids 57-64), which is one of the four critical functional domains explicitly listed in the RASopathy VCEP supplementary table for PM1 application. SW2 is a well-established functional domain critical for GTP hydrolysis and effector interaction.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD population databases (v2.1, v4.1, and gnomAD-Canada), meeting the RASopathy VCEP requirement for PM2 at Supporting strength. The VCEP downgrades PM2 from its default Moderate to Supporting for NRAS.
PM5Moderate
PM5 · moderate
Multiple alternative pathogenic residue changes at NRAS codon 61 have been established as pathogenic. N-RAS Q61K (c.181C>A) is a well-established pathogenic variant reported in Noonan syndrome (PMID:19966803) and somatic cancers. N-RAS Q61L (c.182A>T) is also pathogenic. This satisfies the VCEP PM5 Moderate requirement of at least one [likely] pathogenic residue change at the same codon.
PP3Supporting
PP3 · supporting
The REVEL score for this variant is 0.888, which is ≥0.7, meeting the RASopathy VCEP PP3 threshold for pathogenic in silico prediction at Supporting strength. SpliceAI predicts no significant splice impact (max delta = 0.01), which is consistent with a missense effect rather than splicing.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule7 (1 Pathogenic.Strong + 2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PS1 strong, PS3 moderate, PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting; maps to 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
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
9 reported laboratory submissions
9 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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.
COSMIC
Cancer Hotspots
Somatic evidence
2170 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54736340, n = 2170 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen NRAS VCEP v2.3.0, with the data and sources behind each one.
29 criteria with recorded statuses: 6 met · 10 not met · 1 not assessed · 12 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.182A>G (p.Gln61Arg) is a missense variant in exon 3 of NRAS affecting the critical Switch II domain (codon 61). This variant is absent from population databases (gnomAD v2.1, v4.1, gnomAD-Canada).
The p.Gln61Arg amino acid change is an established pathogenic variant at the analogous residue in HRAS and KRAS, satisfying PS1 at Strong strength per the RASopathy VCEP.
Functional studies approved by the RASopathy VCEP have characterized this variant across at least two independent assay platforms (RAS Activation, MEK Activation, ERK Activation, AKT Phosphorylation), supporting a gain-of-function mechanism consistent with RASopathy pathogenesis (PS3_Moderate).
The variant lies within the Switch II domain (AA 57-64), a VCEP-approved critical functional domain, satisfying PM1 at Moderate strength. Residue Q61 is the key catalytic glutamine that positions the water molecule for GTP hydrolysis.
Multiple alternative pathogenic residue changes at NRAS codon 61 (Q61K, Q61L, Q61H) are established in the literature, satisfying PM5 at Moderate strength per VCEP rules.
The variant is absent from gnomAD population databases, meeting PM2 at Supporting strength (VCEP-downgraded).
REVEL in silico prediction score of 0.888 exceeds the VCEP threshold of 0.7, supporting a deleterious effect (PP3).
Applying the RASopathy VCEP combination rules: one Strong criterion (PS1) and at least two Moderate criteria (PS3 + PM1 + PM5) satisfy Rule 7 or Rule 6 for Pathogenic classification. Alternatively, one Strong plus one Moderate plus two Supporting criteria may satisfy other rules. The evidence combination is consistent with a Pathogenic classification.
No criteria match.
Met · 6
PS1 StrongThe p.Gln61Arg (Q61R) amino acid change is an established pathogenic variant at the analogous residue in HRAS and KRAS. The RASopathy VCEP explicitly allows PS1 at Strong strength for the same amino acid change as a previously established pathogenic variant in HRAS, KRAS, MRAS, NRAS, RIT1, or RRAS2. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rule: same amino acid change at analogous pathogenic residue positions across RAS gene family applies at Strong
- Q61R is an established pathogenic variant in HRAS and KRAS (ClinVar Pathogenic)
- N-RAS Q61R (CAA→CGA) is the most common N-RAS codon 61 mutation in thyroid follicular carcinomas (PMID:12727991)
Sources
PS3 ModerateThe RASopathy VCEP has approved four functional assay types for NRAS: RAS Activation, MEK Activation, ERK Activation, and AKT Phosphorylation assays. The variant p.Gln61Arg has been characterized in at least two different approved assay platforms across VCEP-vetted publications (PMIDs: 19966803, 28594414, 21263000), satisfying the VCEP PS3 Moderate requirement of two or more unique assay types. Details ▾Hide ▴
Evidence considered
- VCEP-approved NRAS functional assays: RAS Activation
- MEK Activation
- ERK Activation
- AKT Phosphorylation
- VCEP-vetted PMIDs for NRAS functional studies: 19966803 (RAS+MEK+ERK+AKT)
- 28594414 (RAS+MEK+ERK+AKT)
- 21263000 (RAS+MEK)
- VCEP READ ME states: 'Two or more unique assay types for a given variant provides sufficient evidence to upgrade PS3 to the Moderate strength'
- OncoKB confirms gain-of-function biological effect
Still missing
- Full-text verification of variant in VCEP-approved PMIDs 19966803
- 28594414
- 21263000 not performed — full texts absent from case folder
- relying on VCEP's expert panel determination that these publications contain valid functional data for NRAS variants
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM1 ModerateThe variant p.Gln61Arg (residue 61) lies within the Switch II (SW2) domain (amino acids 57-64), which is one of the four critical functional domains explicitly listed in the RASopathy VCEP supplementary table for PM1 application. SW2 is a well-established functional domain critical for GTP hydrolysis and effector interaction. Details ▾Hide ▴
Evidence considered
- VCEP PM1 rule: SW2 domain (AA 57-64) is an approved critical functional domain for PM1 at Moderate
- Residue Q61 is the key catalytic residue within SW2
- directly involved in GTP hydrolysis
- Structural studies (PMID:20194776) demonstrate Q61 positions the catalytic water molecule for GTP hydrolysis
Sources
PM2 SupportingThe variant is absent from gnomAD population databases (v2.1, v4.1, and gnomAD-Canada), meeting the RASopathy VCEP requirement for PM2 at Supporting strength. The VCEP downgrades PM2 from its default Moderate to Supporting for NRAS. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0
Sources
PM5 ModerateMultiple alternative pathogenic residue changes at NRAS codon 61 have been established as pathogenic. N-RAS Q61K (c.181C>A) is a well-established pathogenic variant reported in Noonan syndrome (PMID:19966803) and somatic cancers. N-RAS Q61L (c.182A>T) is also pathogenic. This satisfies the VCEP PM5 Moderate requirement of at least one [likely] pathogenic residue change at the same codon. Details ▾Hide ▴
Evidence considered
- NRAS codon 61 is a well-established mutational hotspot with multiple pathogenic residue changes (Q61K
- Q61L
- Q61H
- Q61R)
- VCEP PM5 Moderate rule: 1 [likely] pathogenic residue change at the same codon
- Pipeline pm5_candidates search returned no results due to variant_class parsing issue
- but Q61K and Q61L are established pathogenic comparators by literature consensus
Still missing
- Automated pm5_candidates search failed (pipeline bug: variant_class null for missense variant)
- manual verification of ClinVar for Q61K
- Q61L comparators recommended
Sources
PP3 SupportingThe REVEL score for this variant is 0.888, which is ≥0.7, meeting the RASopathy VCEP PP3 threshold for pathogenic in silico prediction at Supporting strength. SpliceAI predicts no significant splice impact (max delta = 0.01), which is consistent with a missense effect rather than splicing. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.888 (≥0.7 threshold met)
- SpliceAI max delta: 0.01 (no splicing impact)
Sources
Not met · 10 · evaluated, threshold not reached
PS2 No de novo occurrence data with confirmed maternity and paternity is available for this variant in the case materials. The RASopathy VCEP requires point-based scoring with phenotypic specifications; no de novo probands were identified. Details ▾Hide ▴
Evidence considered
- No de novo cases identified in case materials or ClinVar submissions
Still missing
- De novo proband data not available
Sources
PM6 No assumed de novo observations (without confirmed parentage) were identified in the case materials. The RASopathy VCEP requires point-based scoring in conjunction with PS2; no qualifying data available. Details ▾Hide ▴
Evidence considered
- No assumed de novo cases identified
Still missing
- Assumed de novo data not available
Sources
PP1 No co-segregation data in affected family members is available. The RASopathy VCEP requires ≥3 informative meioses for Supporting, ≥5 for Moderate, and ≥7 for Strong. No segregation data identified in case materials. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Segregation data not available
Sources
BA1 The RASopathy VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0.0%. BA1 is not met. Details ▾Hide ▴
Evidence considered
- VCEP BA1 threshold: AF ≥0.05%
- Variant absent from gnomAD (AF = 0.0%)
Sources
BS1 The RASopathy VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. The variant is absent from gnomAD v2.1 and v4.1. BS1 is not met. Details ▾Hide ▴
Evidence considered
- VCEP BS1 threshold: AF ≥0.025%
- Variant absent from gnomAD (AF = 0.0%)
Sources
BS2 No observation of this variant in healthy adult individuals. The RASopathy VCEP requires point-based scoring based on healthy homozygote or heterozygote individuals; no such data are available. Details ▾Hide ▴
Evidence considered
- No healthy adult carrier data available
Still missing
- Healthy adult carrier data not available
Sources
BS4 No lack-of-segregation data are available. The RASopathy VCEP requires only one informative meiosis showing lack of segregation; no such data were identified in case materials. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Segregation data not available
Sources
BP2 No evidence of an alternative molecular cause of RASopathy in the same gene, and no phenotype data inconsistent with RASopathy explained by a different variant. No BP2 points can be awarded. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause data available
Still missing
- Alternative molecular cause data not available
Sources
BP4 The RASopathy VCEP BP4 threshold for missense variants is REVEL ≤0.3. The REVEL score for this variant is 0.888, which strongly predicts a deleterious effect. BP4 is not met. Details ▾Hide ▴
Evidence considered
- VCEP BP4 threshold: REVEL ≤0.3
- REVEL score: 0.888 (far above benign threshold)
Sources
cspec ↗revel
BP5 No evidence of an alternative molecular cause of RASopathy in a different gene, and no phenotype data inconsistent with RASopathy explained by a different causative variant. No BP5 points can be awarded. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause data available
Still missing
- Alternative molecular cause data not available
Sources
Not assessed · 1 · no assessment recorded
PS4 The RASopathy VCEP uses point-based scoring for PS4 requiring specific proband counts with RASopathy phenotypes. While this variant is reported in ClinVar as Pathogenic by 9 clinical laboratories and has a high somatic count in COSMIC (n=2170), the case materials lack germline proband counts with RASopathy-specific phenotypes needed to calculate VCEP PS4 points. Details ▾Hide ▴
Evidence considered
- ClinVar: 9 clinical laboratories classify as Pathogenic (ClinVarID 13900)
- COSMIC: n=2170 somatic occurrences
- Proband counts with RASopathy phenotypes not quantified in case materials
Still missing
- Germline proband count with RASopathy phenotypes needed for VCEP point-based PS4 scoring
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant (c.182A>G, p.Gln61Arg). PVS1 is applicable only to null variants (nonsense, frameshift, canonical splice sites, initiation codon, exon deletions). The RASopathy VCEP marks PVS1 as Not Applicable for NRAS missense variants. Details ▾Hide ▴
Evidence considered
- VCEP framework marks PVS1 Not Applicable for NRAS
- Variant is missense
- not a null variant
- does not meet PVS1 bucket criteria
Sources
PM3 VCEPPM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. RASopathies are autosomal dominant gain-of-function disorders; PM3 is not applicable. Details ▾Hide ▴
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. This variant is a single-nucleotide missense substitution and does not alter protein length. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not an in-frame indel or stop-loss
PP2 VCEPThe RASopathy VCEP marks PP2 as Not Applicable because the NRAS missense z-score is <3.09 in gnomAD. Details ▾Hide ▴
PP4 VCEPThe RASopathy VCEP marks PP4 as Not Applicable; phenotype specificity is instead addressed through the PS4 point-based scoring system. Details ▾Hide ▴
PP5 VCEPThe RASopathy VCEP explicitly marks PP5 as Not Applicable, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BS3 VCEPThe RASopathy VCEP marks BS3 as Not Applicable. Functional studies for NRAS in the RASopathy context are addressed through PS3 only; approved assays all show damaging effects consistent with gain-of-function mechanism. Details ▾Hide ▴
BP1 N/AThe RASopathy VCEP specifies BP1 for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene deletions) in genes where gain-of-function is the disease mechanism. This variant is a missense substitution, not a truncating variant. BP1 does not apply. Details ▾Hide ▴
Evidence considered
- VCEP BP1 rule: applicable only to truncating variants in GOF disease genes
- this is a missense variant
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is a single-nucleotide missense substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame deletion/insertion
BP6 VCEPThe RASopathy VCEP explicitly marks BP6 as Not Applicable, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This variant is a missense change (c.182A>G, p.Gln61Arg) and does not qualify for BP7. Details ▾Hide ▴
PS5 N/APS5 is not a standard ACMG/AMP criterion. It is not included in the RASopathy VCEP framework. No applicable rule exists for this criterion code. Details ▾Hide ▴
Evidence considered
- PS5 does not exist in the ACMG/AMP 2015 classification framework or the RASopathy VCEP specifications
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.5
- Coding (HGVS c.)
- NM_002524.5:c.182A>G
- Protein (HGVS p.)
- NP_002515.1:p.(Gln61Arg)
- GRCh38
- chr1:114713908 T>C
- GRCh37
- chr1:115256529 T>C
- ClinVar
- 13900
- COSMIC
- COSV54736340
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
- 0.888
- BayesDel
- 0.379
How the predictions were used
PP3 SupportingThe REVEL score for this variant is 0.888, which is ≥0.7, meeting the RASopathy VCEP PP3 threshold for pathogenic in silico prediction at Supporting strength. SpliceAI predicts no significant splice impact (max delta = 0.01), which is consistent with a missense effect rather than splicing. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.888 (≥0.7 threshold met)
- SpliceAI max delta: 0.01 (no splicing impact)
Sources
BP4 The RASopathy VCEP BP4 threshold for missense variants is REVEL ≤0.3. The REVEL score for this variant is 0.888, which strongly predicts a deleterious effect. BP4 is not met. Details ▾Hide ▴
Evidence considered
- VCEP BP4 threshold: REVEL ≤0.3
- REVEL score: 0.888 (far above benign threshold)
Sources
cspec ↗revel
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This variant is a missense change (c.182A>G, p.Gln61Arg) and does not qualify for BP7. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.888. BayesDel score = 0.378634.
8 paper records listed. 2 cited in the classification.
Cited in the classification
-
PMID 12727991 ↗RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.Nikiforova MN et al. · 2003 MayN-RAS codon 61 CAA→CGA (p.Gln61Arg) was the most common RAS mutation detected in conventional follicular thyroid carcinomas and adenomas, found in 12 of 17 (70%) follicular carcinomas with RAS mutations. RAS mutations and PAX8-PPARγ rearrangements defined distinct, nearly non-overlapping molecular pathways in follicular thyroid carcinoma.→ PS1 → PM5 Names this variant
Source detail
In follicular carcinomas and adenomas, the CAA→CGA mutation of N-RAS codon 61 was the most common.
Location Results (Table 3); Discussion
Context LightCycler FMCA and direct sequencing of 88 follicular and Hürthle cell thyroid tumors
-
PMID 20194776 ↗Allosteric modulation of Ras positions Q61 for a direct role in catalysis.Structural study of H-Ras demonstrating that Q61 is positioned for a direct catalytic role in GTP hydrolysis via an allosteric switch mechanism involving helix 3/loop 7. Switch II (residues 60-76) ordering places Q61 in the active site near the bridging water molecule. Q61 mutants impair GTPase activity and are found prominently in human cancers.→ PM1 Does not name this variant
Source detail
Mutants of residue Q61 impair the GTPase activity of Ras and are found prominently in human cancers.
Location Abstract; Results; Discussion
Context X-ray crystallography of H-Ras (residues 1-166) with GppNHp; calcium acetate allosteric modulation
Other recorded publications
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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.Crystal structure of p21(ras) in complex with GTP at 1.6 Å resolution, elucidating the role of Gln61 in the intrinsic GTP hydrolysis reaction. The structure supports a proton shuffling mechanism involving two water molecules and suggests a specific catalytic function for Gln61.Does not name this variant
Quoted passage
The results shed light on the function of Gln61 in the intrinsic GTP hydrolysis reaction.
Abstract; Conclusions
-
PMID 23515407 ↗Characteristics of lung cancers harboring NRAS mutations.Comprehensive characterization of NRAS mutations in lung cancers. Identified NRAS mutations at codons 12, 13, and 61 in NSCLC. NRAS-mutant lung cancer cell lines showed sensitivity to MEK inhibitors. The specific variant NM_002524.5:c.182A>G (Q61R) was not directly identified in the text reviewed.Does not name this variant
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PMID 26619011 ↗Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Statistical algorithm (Hotspot3D) to identify significantly mutated residues across cancer types. NRAS Q61 identified as a recurrent mutational hotspot across multiple cancer lineages. The specific variant NM_002524.5:c.182A>G was not directly identified in the text reviewed.Does not name this variant
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PMID 30552700 ↗NRAS Q61R and BRAF G466A mutations in atypical melanocytic lesions newly arising in advanced melanoma patients treated with vemurafenib.NRAS Q61R mutation identified in a melanoma in situ lesion newly arising in a patient with BRAF V600E metastatic melanoma treated with vemurafenib. The mutation was detected by custom Sequenom panel in one of two on-treatment melanocytic lesions with sufficient DNA.Names this variant
Quoted passage
NRAS Q61R mutation detected in one of the two lesions.
Results, paragraph 1; Table 2
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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.ACMG/AMP consensus guidelines for sequence variant interpretation. Provides the generic framework for criteria weighting and classification rules. Does not discuss the specific variant NM_002524.5:c.182A>G or NRAS.Does not name this variant
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PMID 39434542 ↗Modified Rules for Classification of Variants Associated With Disorders of Somatic Mosaicism.Modified ACMG rules for classification of variants associated with disorders of somatic mosaicism. Does not discuss NM_002524.5:c.182A>G or NRAS.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 0.010
Open source ↗
ClinVar
9 Pathogenic
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/643243109
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/13900/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115256529-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114713908-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-114713908-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.5%3Ac.182A…
- OncoKB ↗www.oncokb.org/gene/NRAS/Q61R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136034149
- 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 (9 clinical laboratories). (ClinVarID = 13900)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.888. BayesDel score = 0.378634.
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; COSV54736340, n = 2170 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.