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NM_002386.4(MC1R):c.667C>T (p.Arg223Trp) AND Melanoma, cutaneous malignant, susceptibility to, 5

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Dec 1, 2023
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000470959.12

Allele description [Variation Report for NM_002386.4(MC1R):c.667C>T (p.Arg223Trp)]

NM_002386.4(MC1R):c.667C>T (p.Arg223Trp)

Gene:
MC1R:melanocortin 1 receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16q24.3
Genomic location:
Preferred name:
NM_002386.4(MC1R):c.667C>T (p.Arg223Trp)
HGVS:
  • NC_000016.10:g.89919925C>T
  • NG_012026.1:g.7047C>T
  • NG_027810.1:g.2917C>T
  • NM_002386.4:c.667C>TMANE SELECT
  • NP_002377.4:p.Arg223Trp
  • NP_002377.4:p.Arg223Trp
  • NC_000016.9:g.89986333C>T
  • NM_002386.3:c.667C>T
Protein change:
R223W
Links:
dbSNP: rs372152373
NCBI 1000 Genomes Browser:
rs372152373
Molecular consequence:
  • NM_002386.4:c.667C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Melanoma, cutaneous malignant, susceptibility to, 5
Synonyms:
Cutaneous malignant melanoma 5
Identifiers:
MONDO: MONDO:0013133; MedGen: C2751295; Orphanet: 618; OMIM: 613099

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000544754Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Dec 1, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001279599Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)		Benign
(Apr 28, 2017) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Variants in melanocortin 1 receptor gene contribute to risk of melanoma--a direct sequencing analysis in a Texas population.

Guan X, Niu J, Liu Z, Wang LE, Amos CI, Lee JE, Gershenwald JE, Grimm EA, Wei Q.

Pigment Cell Melanoma Res. 2013 May;26(3):422-5. doi: 10.1111/pcmr.12070. Epub 2013 Feb 19. No abstract available.

PubMed [citation]
PMID:
23360207
PMCID:
PMC3721512

A large French case-control study emphasizes the role of rare Mc1R variants in melanoma risk.

Hu HH, Benfodda M, Dumaz N, Gazal S, Descamps V, Bourillon A, Basset-Seguin N, Riffault A, Ezzedine K, Bagot M, Bensussan A, Saiag P, Grandchamp B, Soufir N.

Biomed Res Int. 2014;2014:925716. doi: 10.1155/2014/925716. Epub 2014 Apr 10.

PubMed [citation]
PMID:
24982914
PMCID:
PMC4003837
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544754.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 223 of the MC1R protein (p.Arg223Trp). This variant is present in population databases (rs372152373, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 20043015, 23360207, 24982914). ClinVar contains an entry for this variant (Variation ID: 406213). 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. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV001279599.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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 rule this variant out of causing disease. Therefore, this variant is classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024