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 from a glutamine to a lysine at position 61 of the protein; NP_002515.1(NRAS):p.(Gln61Lys). The glutamine at this position has very high conservation (100 vertebrates, UCSC), and is located within the switch II region (Cirstea, I. C. et al. (2010)). In silico software predicts this variant to be damaging (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in multiple patients with congenital melanocytic naevi (ClinVar, Kinsler, V. A. et al. (2013)). In addition, functional studies show that this variant causes melanocyte survival and growth in the epidermis (Li, A. et al. (2012)). Different variants in the same codon resulting in changes to histidine, leucine, arginine, proline and glutamic acid, have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
ClinVar Genomic variation as it relates to human health
NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(2); Uncertain significance(1)
Pathogenic(2); Uncertain significance(1)
3 out of 7 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
7
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Oncogenic
This classification is based on the single submission received
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
1
Variant Details
- Identifiers
-
NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)
Variation ID: 73058 Accession: VCV000073058.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p13.2 1: 114713909 (GRCh38) [ NCBI UCSC ] 1: 115256530 (GRCh37) [ NCBI UCSC ] 1: 115058053 (NCBI36) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2015 Apr 20, 2025 May 21, 2020 Somatic - Oncogenicity Aug 11, 2024 Mar 11, 2025 Mar 4, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002524.5:c.181C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002515.1:p.Gln61Lys missense NC_000001.11:g.114713909G>T NC_000001.10:g.115256530G>T NG_007572.1:g.7986C>A LRG_92:g.7986C>A P01111:p.Gln61Lys - Protein change
- Q61K
- Other names
- -
- Canonical SPDI
- NC_000001.11:114713908:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| NRAS | - | - |
GRCh38 GRCh37 |
300 | 324 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
May 21, 2020 | RCV000114746.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2013 | RCV000144964.5 | |
| drug response (1) |
no assertion criteria provided
|
Nov 27, 2017 | RCV000626456.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 29, 2018 | RCV000696329.5 | |
|
Vascular Tumors Including Pyogenic Granuloma
|
Likely pathogenic (1) |
no assertion criteria provided
|
Feb 19, 2015 | RCV000662267.3 |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2018 | RCV001092890.26 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 21, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Large congenital melanocytic nevus
(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 |
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)
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 from a glutamine to a lysine at position 61 of the protein; NP_002515.1(NRAS):p.(Gln61Lys). The glutamine at this position has very high conservation (100 vertebrates, UCSC), and is located within the switch II region (Cirstea, I. C. et al. (2010)). In silico software predicts this variant to be damaging (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in multiple patients with congenital melanocytic naevi (ClinVar, Kinsler, V. A. et al. (2013)). In addition, functional studies show that this variant causes melanocyte survival and growth in the epidermis (Li, A. et al. (2012)). Different variants in the same codon resulting in changes to histidine, leucine, arginine, proline and glutamic acid, have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
|
|
|
Pathogenic
(Sep 01, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249621.29
First in ClinVar: May 12, 2020 Last updated: Apr 20, 2025 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jan 29, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: curation
|
Rasopathy
Affected status: unknown
Allele origin:
unknown
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000824885.2
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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)
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 small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). While this variant has been published in the literature (PMID: 23392294), it has not been reported in the germline of an individual with NRAS-related disease. ClinVar contains an entry for this variant (Variation ID: 73058). This variant has been reported as a recurrent variant in melanoma tumors (PMID: 23392294), colorectal tumors (PMID: 27050078, 23400451), thyroid tumors (PMID: 28780248), squamous cell lung tumors (PMID: 25348872), neuroblastoma tumors (PMID: 26821351), and gynecological tumors (PMID: 24671188). Experimental studies have shown that this missense change p.Gln61Lys, results in cytoskeletal changes in melanocyte cell lines, reduces apoptosis, and results in hyperpigmented skin in transgenic mice who develop cutaneous metastasizing melanoma (PMID: 22718121, 18668139, 15899789). However, in a thyroid epithelial cell line, this variant alone resulted in zero tumor instances (PMID: 10821536). In zebrafish, expression of human NRAS p.Q61K in melanocytes results in the growth of pigmented lesions that rarely progress to melanoma. (PMID: 24148783). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Pathogenic
(Sep 01, 2013)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
MELANOCYTIC NEVUS SYNDROME, CONGENITAL, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000148629.3
First in ClinVar: Apr 19, 2014 Last updated: Oct 11, 2015 |
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)
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 samples from 8 of 13 patients with congenital melanocytic nevus syndrome (CMNS; 137550), including 4 with neurocutaneous melanosis (NCMS; 249400), Kinsler et al. (2013) identified a somatic heterozygous c.181C-A transversion in the NRAS gene, resulting in a gln61-to-lys (Q61K) substitution in the guanosine triphosphate-binding domain. The mutation was predicted to result in constitutive activation of NRAS. Neurologic samples from 5 patients from whom tissue was available were positive for a somatic Q61K mutation, and the same mutation was present in both neurologic and skin samples when available. Kinsler et al. (2013) concluded that multiple congenital melanocytic nevi and neuromelanosis, as well as associated nonmelanocytic CNS lesions, result from somatic mosaicism, and that the mutation probably occurs in a progenitor cell in the developing neural crest or neuroectoderm. The findings also suggested that the mutation may be lethal in the germline. (less)
|
|
|
Pathogenic
(Sep 01, 2013)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
NEUROCUTANEOUS MELANOSIS, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000191991.2
First in ClinVar: Nov 22, 2014 Last updated: Oct 11, 2015 |
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)
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 samples from 8 of 13 patients with congenital melanocytic nevus syndrome (CMNS; 137550), including 4 with neurocutaneous melanosis (NCMS; 249400), Kinsler et al. (2013) identified a somatic heterozygous c.181C-A transversion in the NRAS gene, resulting in a gln61-to-lys (Q61K) substitution in the guanosine triphosphate-binding domain. The mutation was predicted to result in constitutive activation of NRAS. Neurologic samples from 5 patients from whom tissue was available were positive for a somatic Q61K mutation, and the same mutation was present in both neurologic and skin samples when available. Kinsler et al. (2013) concluded that multiple congenital melanocytic nevi and neuromelanosis, as well as associated nonmelanocytic CNS lesions, result from somatic mosaicism, and that the mutation probably occurs in a progenitor cell in the developing neural crest or neuroectoderm. The findings also suggested that the mutation may be lethal in the germline. (less)
|
|
|
drug response
Likely response to RAS inhibitors.
(Nov 27, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
RAS Inhibitor response
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.
|
|
|
Likely pathogenic
(Feb 19, 2015)
N
Not contributing to aggregate classification
|
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 |
Zygosity: Single Heterozygote
|
Comment:
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 small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). While this variant has been published in the literature (PMID: 23392294), it has not been reported in the germline of an individual with NRAS-related disease. ClinVar contains an entry for this variant (Variation ID: 73058). This variant has been reported as a recurrent variant in melanoma tumors (PMID: 23392294), colorectal tumors (PMID: 27050078, 23400451), thyroid tumors (PMID: 28780248), squamous cell lung tumors (PMID: 25348872), neuroblastoma tumors (PMID: 26821351), and gynecological tumors (PMID: 24671188). Experimental studies have shown that this missense change p.Gln61Lys, results in cytoskeletal changes in melanocyte cell lines, reduces apoptosis, and results in hyperpigmented skin in transgenic mice who develop cutaneous metastasizing melanoma (PMID: 22718121, 18668139, 15899789). However, in a thyroid epithelial cell line, this variant alone resulted in zero tumor instances (PMID: 10821536). In zebrafish, expression of human NRAS p.Q61K in melanocytes results in the growth of pigmented lesions that rarely progress to melanoma. (PMID: 24148783). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Germline Functional Evidence
| 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. |
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 from a glutamine to a lysine at position 61 of the protein; NP_002515.1(NRAS):p.(Gln61Lys). The glutamine at this position has very high conservation (100 vertebrates, UCSC), and is located within the switch II region (Cirstea, I. C. et al. (2010)). In silico software predicts this variant to be damaging (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in multiple patients with congenital melanocytic naevi (ClinVar, Kinsler, V. A. et al. (2013)). In addition, functional studies show that this variant causes melanocyte survival and growth in the epidermis (Li, A. et al. (2012)). Different variants in the same codon resulting in changes to histidine, leucine, arginine, proline and glutamic acid, have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
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 small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). While this variant has been published in the literature (PMID: 23392294), it has not been reported in the germline of an individual with NRAS-related disease. ClinVar contains an entry for this variant (Variation ID: 73058). This variant has been reported as a recurrent variant in melanoma tumors (PMID: 23392294), colorectal tumors (PMID: 27050078, 23400451), thyroid tumors (PMID: 28780248), squamous cell lung tumors (PMID: 25348872), neuroblastoma tumors (PMID: 26821351), and gynecological tumors (PMID: 24671188). Experimental studies have shown that this missense change p.Gln61Lys, results in cytoskeletal changes in melanocyte cell lines, reduces apoptosis, and results in hyperpigmented skin in transgenic mice who develop cutaneous metastasizing melanoma (PMID: 22718121, 18668139, 15899789). However, in a thyroid epithelial cell line, this variant alone resulted in zero tumor instances (PMID: 10821536). In zebrafish, expression of human NRAS p.Q61K in melanocytes results in the growth of pigmented lesions that rarely progress to melanoma. (PMID: 24148783). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| A restricted spectrum of NRAS mutations causes Noonan syndrome. | Cirstea IC | Nature genetics | 2010 | PMID: 19966803 |
| 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 |
| Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background. | Ackermann J | Cancer research | 2005 | PMID: 15899789 |
| 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 |
| click to load more citations click to collapse | ||||
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Mar 4, 2025 | RCV004668769.2 |
Submissions - Somatic
|
Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094176.2
First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025 |
|
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 from a glutamine to a lysine at position 61 of the protein; NP_002515.1(NRAS):p.(Gln61Lys). The glutamine at this position has very high conservation (100 vertebrates, UCSC), and is located within the switch II region (Cirstea, I. C. et al. (2010)). In silico software predicts this variant to be damaging (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in multiple patients with congenital melanocytic naevi (ClinVar, Kinsler, V. A. et al. (2013)). In addition, functional studies show that this variant causes melanocyte survival and growth in the epidermis (Li, A. et al. (2012)). Different variants in the same codon resulting in changes to histidine, leucine, arginine, proline and glutamic acid, have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
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 small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). While this variant has been published in the literature (PMID: 23392294), it has not been reported in the germline of an individual with NRAS-related disease. ClinVar contains an entry for this variant (Variation ID: 73058). This variant has been reported as a recurrent variant in melanoma tumors (PMID: 23392294), colorectal tumors (PMID: 27050078, 23400451), thyroid tumors (PMID: 28780248), squamous cell lung tumors (PMID: 25348872), neuroblastoma tumors (PMID: 26821351), and gynecological tumors (PMID: 24671188). Experimental studies have shown that this missense change p.Gln61Lys, results in cytoskeletal changes in melanocyte cell lines, reduces apoptosis, and results in hyperpigmented skin in transgenic mice who develop cutaneous metastasizing melanoma (PMID: 22718121, 18668139, 15899789). However, in a thyroid epithelial cell line, this variant alone resulted in zero tumor instances (PMID: 10821536). In zebrafish, expression of human NRAS p.Q61K in melanocytes results in the growth of pigmented lesions that rarely progress to melanoma. (PMID: 24148783). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer. | Loree JM | Clinical cancer research : an official journal of the American Association for Cancer Research | 2021 | PMID: 34117033 |
| Mutation-specific effects of NRAS oncogenes in colorectal cancer cells. | Kuhn N | Advances in biological regulation | 2021 | PMID: 33431353 |
| 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 |
Text-mined citations for rs121913254 ...
HelpThese 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 Apr 20, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.