VCV000321435.11 - ClinVar

NM_002386.4(MC1R):c.637C>T (p.Arg213Trp)

Germline

Classification

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.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002386.4(MC1R):c.637C>T (p.Arg213Trp)

Variation ID: 321435 Accession: VCV000321435.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89919895 (GRCh38) [ NCBI UCSC ] 16: 89986303 (GRCh37) [ 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	Dec 6, 2016	Feb 28, 2024	Dec 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002386.4:c.637C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002377.4:p.Arg213Trp	missense
NC_000016.10:g.89919895C>T
NC_000016.9:g.89986303C>T
NG_012026.1:g.7017C>T
NG_027810.1:g.2887C>T

... more HGVS ... less HGVS

Protein change

R213W

Other names

Canonical SPDI

NC_000016.10:89919894:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00080 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00034

The Genome Aggregation Database (gnomAD), exomes 0.00035

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00048

The Genome Aggregation Database (gnomAD) 0.00066

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00080

Trans-Omics for Precision Medicine (TOPMed) 0.00097

Links

ClinGen: CA8255693 dbSNP: rs200000734 VarSome

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
Gene	OMIM	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.
MC1R		-	-	GRCh38 GRCh37	499	559

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.
Melanoma, cutaneous malignant, susceptibility to, 5	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Dec 22, 2023	RCV000476253.14

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.
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Melanoma, cutaneous malignant, susceptibility to, 5 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000399967.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (9) PubMed: 19799798‚ 18402696‚ 15221796‚ 23522749‚ 14961558‚ 19269164‚ 20876876‚ 18803811‚ 19493000 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (Dec 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Melanoma, cutaneous malignant, susceptibility to, 5 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000544752.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (9) PubMed: 15221796‚ 15998953‚ 18067130‚ 19799798‚ 23360207‚ 23522749‚ 23647022‚ 24982914‚ 25284244 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 213 of the MC1R protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 213 of the MC1R protein (p.Arg213Trp). This variant is present in population databases (rs200000734, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 15221796, 15998953, 18067130, 19799798, 23360207, 23522749, 23647022, 24982914, 25284244). ClinVar contains an entry for this variant (Variation ID: 321435). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC1R protein function. Experimental studies have shown that this missense change affects MC1R function (PMID: 23522749). 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)

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 213 of the MC1R protein (p.Arg213Trp). This variant is present in population databases (rs200000734, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 15221796, 15998953, 18067130, 19799798, 23360207, 23522749, 23647022, 24982914, 25284244). ClinVar contains an entry for this variant (Variation ID: 321435). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC1R protein function. Experimental studies have shown that this missense change affects MC1R function (PMID: 23522749). 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The melanocortin 1 receptor (Mc1r) variants do not account for the co-occurrence of Parkinson's disease and malignant melanoma.	Elincx-Benizri S	Journal of molecular neuroscience : MN	2014	PMID: 25284244
A large French case-control study emphasizes the role of rare Mc1R variants in melanoma risk.	Hu HH	BioMed research international	2014	PMID: 24982914
Distribution of MC1R variants among melanoma subtypes: p.R163Q is associated with lentigo maligna melanoma in a Mediterranean population.	Puig-Butillé JA	The British journal of dermatology	2013	PMID: 23647022
Melanoma risk associated with MC1R gene variants in Latvia and the functional analysis of rare variants.	Ozola A	Cancer genetics	2013	PMID: 23522749
Variants in melanocortin 1 receptor gene contribute to risk of melanoma--a direct sequencing analysis in a Texas population.	Guan X	Pigment cell & melanoma research	2013	PMID: 23360207
Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.	Demenais F	Journal of the National Cancer Institute	2010	PMID: 20876876
Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy.	Casula M	BMC cancer	2009	PMID: 19799798
Germline variation of the melanocortin-1 receptor does not explain shared risk for melanoma and thyroid cancer.	Bauer J	Experimental dermatology	2009	PMID: 19493000
MC1R variant alleles and malignant melanoma risk in Israel.	Galore-Haskel G	European journal of cancer (Oxford, England : 1990)	2009	PMID: 19269164
Prevalence of variations in melanoma susceptibility genes among Slovenian melanoma families.	Peric B	BMC medical genetics	2008	PMID: 18803811
Nucleotide diversity and population differentiation of the melanocortin 1 receptor gene, MC1R.	Savage SA	BMC genetics	2008	PMID: 18402696
MC1R variants associated susceptibility to basal cell carcinoma of skin: interaction with host factors and XRCC3 polymorphism.	Scherer D	International journal of cancer	2008	PMID: 18067130
MC1R, ASIP, and DNA repair in sporadic and familial melanoma in a Mediterranean population.	Landi MT	Journal of the National Cancer Institute	2005	PMID: 15998953
Novel MC1R variants in Ligurian melanoma patients and controls.	Pastorino L	Human mutation	2004	PMID: 15221796
Identification of four novel melanocortin 1 receptor (MC1R) gene variants in a Mediterranean population.	Fargnoli MC	Human mutation	2003	PMID: 14961558
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Text-mined citations for rs200000734 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002386.4(MC1R):c.637C>T (p.Arg213Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200000734 ...