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NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)

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Interpretation:
Conflicting interpretations of pathogenicity​

Pathogenic(2); Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
26
First in ClinVar:
Oct 11, 2015
Most recent Submission:
Nov 20, 2023
Last evaluated:
May 21, 2020
Accession:
VCV000073058.21
Variation ID:
73058
Description:
single nucleotide variant
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NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)

Allele ID
83949
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1p13.2
Genomic location
1: 114713909 (GRCh38) GRCh38 UCSC
1: 115256530 (GRCh37) GRCh37 UCSC
1: 115058053 (NCBI36) NCBI36 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_002524.5:c.181C>A MANE Select NP_002515.1:p.Gln61Lys missense
NC_000001.11:g.114713909G>T
NC_000001.10:g.115256530G>T
... more HGVS
Protein change
Q61K
Other names
-
Canonical SPDI
NC_000001.11:114713908:G:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Links
ClinGen: CA151263
UniProtKB: P01111#VAR_006846
OMIM: 164790.0008
dbSNP: rs121913254
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 2 criteria provided, single submitter May 21, 2020 RCV000114746.8
Pathogenic 1 no assertion criteria provided Sep 1, 2013 RCV000144964.5
not provided 1 no assertion provided Mar 10, 2016 RCV000423656.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000444882.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000418269.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000418907.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000431313.3
Pathogenic 1 no assertion criteria provided Oct 2, 2014 RCV000434388.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000435041.3
Pathogenic 1 no assertion criteria provided Oct 2, 2014 RCV000425440.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000426976.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000428264.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000428499.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000436588.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000423012.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000441559.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000433274.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000436806.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000443974.3
Likely pathogenic 1 no assertion criteria provided May 31, 2016 RCV000441348.3
Pathogenic 1 no assertion criteria provided May 31, 2016 RCV000444538.3
drug response 1 no assertion criteria provided Nov 27, 2017 RCV000626456.3
Vascular Tumors Including Pyogenic Granuloma
Likely pathogenic 1 no assertion criteria provided Feb 19, 2015 RCV000662267.3
Uncertain significance 1 criteria provided, single submitter Jan 29, 2018 RCV000696329.3
Pathogenic 1 criteria provided, single submitter Sep 1, 2018 RCV001092890.14
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
NRAS - - GRCh38
GRCh37
258 281

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter More information
Uncertain significance
(Jan 29, 2018)
criteria provided, single submitter
Method: curation
Affected status: unknown
Allele origin: unknown
Invitae
Accession: SCV000824885.2
First in ClinVar: Oct 10, 2018
Last updated: Oct 10, 2018
Publications:
PubMed (13)
Comment:
This sequence change replaces glutamine with lysine at codon 61 of the NRAS protein (p.Gln61Lys). The glutamine residue is highly conserved and there is a … (more)
Pathogenic
(May 21, 2020)
criteria provided, single submitter
Method: clinical testing
(Autosomal dominant inheritance)
Affected status: yes
Allele origin: germline
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769261.1
First in ClinVar: Dec 24, 2022
Last updated: Dec 24, 2022
Publications:
PubMed (3)
PubMed: 199668032271812123392294
Comment:
A heterozygous missense variant was identified, NM_002524.3(NRAS):c.181C>A in exon 3 of the NRAS gene. This substitution is predicted to create a minor amino acid change … (more)
Pathogenic
(Sep 01, 2018)
criteria provided, single submitter
Method: clinical testing
Affected status: yes
Allele origin: germline
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249621.17
First in ClinVar: May 12, 2020
Last updated: Nov 20, 2023
Number of individuals with the variant: 1
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503651.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Pathogenic
(Oct 02, 2014)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503649.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (12)
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503650.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (8)
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503653.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Pathogenic
(Oct 02, 2014)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503654.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (3)
PubMed: 124609182351540718948947
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503652.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503655.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503657.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503656.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (2)
PubMed: 2661901119657110
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503664.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503658.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503659.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503660.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503665.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
  • - None
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503666.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Pathogenic
(Sep 01, 2013)
no assertion criteria provided
Method: literature only
Affected status: not provided
Allele origin: somatic
OMIM
Accession: SCV000148629.3
First in ClinVar: Apr 19, 2014
Last updated: Oct 11, 2015
Publications:
PubMed (2)
PubMed: 1863343823392294
Comment on evidence:
Dessars et al. (2009) identified a somatic gln61-to-lys (Q61K) mutation in the NRAS gene in 14 of 27 congenital melanocytic nevi (137550). In affected skin … (more)
Pathogenic
(Sep 01, 2013)
no assertion criteria provided
Method: literature only
Affected status: not provided
Allele origin: somatic
OMIM
Accession: SCV000191991.2
First in ClinVar: Nov 22, 2014
Last updated: Oct 11, 2015
Publications:
PubMed (2)
PubMed: 1863343823392294
Comment on evidence:
Dessars et al. (2009) identified a somatic gln61-to-lys (Q61K) mutation in the NRAS gene in 14 of 27 congenital melanocytic nevi (137550). In affected skin … (more)
Likely pathogenic
(Feb 19, 2015)
no assertion criteria provided
Method: literature only
  • - Vascular Tumors Including Pyogenic Granuloma
Affected status: yes
Allele origin: somatic
Yale Center for Mendelian Genomics, Yale University
Accession: SCV000784595.1
First in ClinVar: Jul 14, 2018
Last updated: Jul 14, 2018
Publications:
PubMed (1)
PubMed: 25695684
Zygosity: 1 Single Heterozygote
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503661.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503667.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
Likely pathogenic
(May 31, 2016)
no assertion criteria provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503663.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26619011
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A
drug response
Likely response to RAS inhibitors.
(Nov 27, 2017)
no assertion criteria provided
Method: clinical testing
Drug used for Cancer
Affected status: yes
Allele origin: somatic
Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust
Accession: SCV000734846.1
First in ClinVar: May 06, 2018
Last updated: May 06, 2018
Method: PCR-Free library Preparation on germline and tumour. Data analyzed after Tumour-Normal Substraction.
not provided
(Mar 10, 2016)
no assertion provided
Method: literature only
(Somatic mutation)
Affected status: yes
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000503662.1
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Publications:
PubMed (1)
PubMed: 26821351
Other databases
http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Invasive follicular variant of papillary thyroid cancer harboring the NRAS mutation Q61K and presenting with bone metastasis-A case report. Mehrzad R International journal of surgery case reports 2017 PMID: 28780248
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Mutation profiling in chinese patients with metastatic colorectal cancer and its correlation with clinicopathological features and anti-EGFR treatment response. Li ZZ Oncotarget 2016 PMID: 27050078
Targeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma. Kiessling MK PloS one 2016 PMID: 26821351
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Chang MT Nature biotechnology 2016 PMID: 26619011
Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma. Lim YH The Journal of investigative dermatology 2015 PMID: 25695684
Prospective genetic profiling of squamous cell lung cancer and adenosquamous carcinoma in Japanese patients by multitarget assays. Kenmotsu H BMC cancer 2014 PMID: 25348872
Designing a high-throughput somatic mutation profiling panel specifically for gynaecological cancers. Spaans VM PloS one 2014 PMID: 24671188
The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models. Yen J Genome biology 2013 PMID: 24148783
Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Morris EJ Cancer discovery 2013 PMID: 23614898
Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. Trunzer K Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013 PMID: 23569304
Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma. Haarberg HE Molecular cancer therapeutics 2013 PMID: 23538902
Characteristics of lung cancers harboring NRAS mutations. Ohashi K Clinical cancer research : an official journal of the American Association for Cancer Research 2013 PMID: 23515407
MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Ascierto PA The Lancet. Oncology 2013 PMID: 23414587
Bevacizumab-based treatment in colorectal cancer with a NRAS Q61K mutation. Janku F Targeted oncology 2013 PMID: 23400451
Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. Kinsler VA The Journal of investigative dermatology 2013 PMID: 23392294
First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Martinez-Garcia M Clinical cancer research : an official journal of the American Association for Cancer Research 2012 PMID: 22761467
Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism. Li A The Journal of investigative dermatology 2012 PMID: 22718121
PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers. Janku F PloS one 2011 PMID: 21829508
Development of molecular biomarkers in individualized treatment of colorectal cancer. De Mattos-Arruda L Clinical colorectal cancer 2011 PMID: 21729679
Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Vaughn CP Genes, chromosomes & cancer 2011 PMID: 21305640
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nazarian R Nature 2010 PMID: 21107323
NRAS mutations are rare in colorectal cancer. Irahara N Diagnostic molecular pathology : the American journal of surgical pathology, part B 2010 PMID: 20736745
Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. De Roock W The Lancet. Oncology 2010 PMID: 20619739
RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Poulikakos PI Nature 2010 PMID: 20179705
RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Hatzivassiliou G Nature 2010 PMID: 20130576
A restricted spectrum of NRAS mutations causes Noonan syndrome. Cirstea IC Nature genetics 2010 PMID: 19966803
Recurring mutations found by sequencing an acute myeloid leukemia genome. Mardis ER The New England journal of medicine 2009 PMID: 19657110
Active N-Ras and B-Raf inhibit anoikis by downregulating Bim expression in melanocytic cells. Goldstein NB The Journal of investigative dermatology 2009 PMID: 18668139
Genotypic and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis. Dessars B The Journal of investigative dermatology 2009 PMID: 18633438
Somatic mutations affect key pathways in lung adenocarcinoma. Ding L Nature 2008 PMID: 18948947
Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. Adjei AA Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 PMID: 18390968
AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Davies BR Molecular cancer therapeutics 2007 PMID: 17699718
BRAF mutation predicts sensitivity to MEK inhibition. Solit DB Nature 2006 PMID: 16273091
Distinct sets of genetic alterations in melanoma. Curtin JA The New England journal of medicine 2005 PMID: 16291983
Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background. Ackermann J Cancer research 2005 PMID: 15899789
BRAF and RAS mutations in human lung cancer and melanoma. Brose MS Cancer research 2002 PMID: 12460918
Human N-ras, TRK-T1, and RET/PTC3 oncogenes, driven by a thyroglobulin promoter, differently affect the expression of differentiation markers and the proliferation of thyroid epithelial cells. Portella G Oncology research 1999 PMID: 10821536
Ras mutations in human melanoma: a marker of malignant progression. Ball NJ The Journal of investigative dermatology 1994 PMID: 8120410
N-ras mutations in human cutaneous melanoma from sun-exposed body sites. van 't Veer LJ Molecular and cellular biology 1989 PMID: 2674680
http://docm.genome.wustl.edu/variants/ENST00000369535:c.181C>A - - - -

Text-mined citations for rs121913254...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 20, 2023