NM_002386.4(MC1R):c.653C>G (p.Ala218Gly) AND Melanoma, cutaneous malignant, susceptibility to, 5

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 4, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001119089.10

Allele description

NM_002386.4(MC1R):c.653C>G (p.Ala218Gly)

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.653C>G (p.Ala218Gly)

HGVS:

NC_000016.10:g.89919911C>G
NG_012026.1:g.7033C>G
NG_027810.1:g.2903C>G
NM_002386.4:c.653C>GMANE SELECT
NP_002377.4:p.Ala218Gly
NC_000016.9:g.89986319C>G
NM_002386.3:c.653C>G

Protein change:

A218G

Links:

dbSNP: rs749385653

NCBI 1000 Genomes Browser:

rs749385653

Molecular consequence:

NM_002386.4:c.653C>G - 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

Recent activity

Clear Turn Off Turn On

PREDICTED: Canis lupus familiaris cholinergic receptor nicotinic beta 2 subunit ...
PREDICTED: Canis lupus familiaris cholinergic receptor nicotinic beta 2 subunit (CHRNB2), transcript variant X2, mRNA
gi|1953085862|ref|XM_038543222.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001277432	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001491374	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 4, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20876876, 16982779, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001277432

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001491374

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 4, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.

Demenais F, Mohamdi H, Chaudru V, Goldstein AM, Newton Bishop JA, Bishop DT, Kanetsky PA, Hayward NK, Gillanders E, Elder DE, Avril MF, Azizi E, van Belle P, Bergman W, Bianchi-Scarrà G, Bressac-de Paillerets B, Calista D, Carrera C, Hansson J, Harland M, Hogg D, Höiom V, et al.

J Natl Cancer Inst. 2010 Oct 20;102(20):1568-83. doi: 10.1093/jnci/djq363. Epub 2010 Sep 28.

PubMed [citation]

PMID:: 20876876
PMCID:: PMC2957428

Population-based study of natural variation in the melanocortin-1 receptor gene and melanoma.

Kanetsky PA, Rebbeck TR, Hummer AJ, Panossian S, Armstrong BK, Kricker A, Marrett LD, Millikan RC, Gruber SB, Culver HA, Zanetti R, Gallagher RP, Dwyer T, Busam K, From L, Mujumdar U, Wilcox H, Begg CB, Berwick M.

Cancer Res. 2006 Sep 15;66(18):9330-7.

PubMed [citation]

PMID:: 16982779

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001277432.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001491374.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with melanoma (PMID: 20876876, 16982779). This variant is present in population databases (rs749385653, ExAC 0.002%). This sequence change replaces alanine with glycine at codon 218 of the MC1R protein (p.Ala218Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

ClinVar

Relating variation to medicine