NM_002386.4:c.880G>C

Variant names:

• chr16-89920138-G-C
• rs1805009
• NM_002386.4:c.880G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_002386.4(MC1R):​c.880G>C​(p.Asp294His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,770 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D294Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 33)
  • Exomes 𝑓: 0.019 (338 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:2 U:1 B:7 O:2
• Conservation: PhyloP100: 9.84
• Publications: 309 publications found

Genes affected

MC1R (HGNC:6929): (melanocortin 1 receptor) This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation. [provided by RefSeq, Jul 2008]

ENSG00000198211 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.010107994).
• BP6: Variant 16-89920138-G-C is Benign according to our data. Variant chr16-89920138-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 14307.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1658/152138) while in subpopulation NFE AF = 0.0182 (1240/67986). AF 95% confidence interval is 0.0174. There are 28 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1658 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002386.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	NM_002386.4	MANE Select	c.880G>C	p.Asp294His	missense	Exon 1 of 1	NP_002377.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	ENST00000555147.2	TSL:6 MANE Select	c.880G>C	p.Asp294His	missense	Exon 1 of 1	ENSP00000451605.1
	ENSG00000198211	ENST00000556922.1	TSL:2	c.880G>C	p.Asp294His	missense	Exon 1 of 5	ENSP00000451560.1
	MC1R	ENST00000555427.1	TSL:5	c.880G>C	p.Asp294His	missense	Exon 3 of 4	ENSP00000451760.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1658 AN: 152022 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00909 AC: 2263 AN: 249066 AF XY: 0.00905

Gnomad AFR exome AF: 0.00311

Gnomad AMR exome AF: 0.00730

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0188 AC: 27485 AN: 1461632 Hom.: 338 Cov.: 35 AF XY: 0.0181 AC XY: 13181 AN XY: 727096

African (AFR) AF: 0.00275 AC: 92 AN: 33480

American (AMR) AF: 0.00742 AC: 332 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00229 AC: 122 AN: 53362

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0231 AC: 25700 AN: 1111836

Other (OTH) AF: 0.0193 AC: 1165 AN: 60372

GnomAD4 genome AF: 0.0109 AC: 1658 AN: 152138 Hom.: 28 Cov.: 33 AF XY: 0.00964 AC XY: 717 AN XY: 74368

African (AFR) AF: 0.00414 AC: 172 AN: 41500

American (AMR) AF: 0.0116 AC: 177 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1240 AN: 67986

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0137 Hom.: 10

Bravo AF: 0.0118

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0221 AC: 85

ESP6500AA AF: 0.00686 AC: 29

ESP6500EA AF: 0.0207 AC: 176

ExAC AF: 0.00853 AC: 1033

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0182

EpiControl AF: 0.0187

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:2 Uncertain:1 Benign:7 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Considered a low risk allele, case control studies suggest this variant is associated with early onset cutaneous melanoma (Cust et al., 2012); Reported in association with red hair, fair skin, increased risk for melanoma, increased risk of photoaging and congenital melanocytic nevi (Puig-Butille et al., 2013; Kinsler et al., 2012; Ibarrola-Villava et al., 2014); Functional characterization of the variant show decreased ability to stimulate cAMP production, and altered cell surface expression (Schioth et al., 1999; Sanchez-Laorden et al., 2009); Observed in 920/66568 (1.4%) alleles from individuals of European background, including 6 unrelated homozygous individuals in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22464597, 12789280, 26103569, 26197705, 10403794, 24665948, 19799798, 24660985, 11875032, 17616515, 18366057, 19452503, 22572819, 24335900, 19656326, 7581459, 23647022, 22095472, 9302268, 11179997, 30531825, 31382929, 30414346, 14709592, 11500805)

Mar 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MC1R p.Asp294His variant has been reported in the literature multiple times in association with melanoma development, red hair and fair skin (Raimondi_2008_PMID:18366057; Zorina-Lichtenwalter_2019_PMID:30657907). The variant was identified in dbSNP (ID: rs1805009), LOVD 3.0 and ClinVar (classified as benign by Invitae, as likely benign by Prevention Genetics and Illumina, as likely pathogenic by Yale Center for Mendelian Genomics and University of Washington Center for Mendelian Genomics, and as pathogenic by GeneDx). The variant was identified in control databases in 2568 of 280442 chromosomes (23 homozygous) at a frequency of 0.009157 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2082 of 128324 chromosomes (freq: 0.01622), Other in 78 of 7136 chromosomes (freq: 0.01093), Latino in 256 of 35366 chromosomes (freq: 0.007239), African in 82 of 24150 chromosomes (freq: 0.003395), European (Finnish) in 53 of 24992 chromosomes (freq: 0.002121) and Ashkenazi Jewish in 17 of 10346 chromosomes (freq: 0.001643), but was not observed in the East Asian or South Asian populations. The p.D294H variant was found to have a dominant negative effect on MC1R cAMP signialling but had normal cell surface expression (Beaumont_2007_PMID:17616515). The p.Asp294 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tyrosinase-positive oculocutaneous albinism Pathogenic:1

Sep 22, 2015

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Skin and Hair Hypopigmentation Pathogenic:1

Sep 22, 2015

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

MC1R-related disorder Benign:1

Apr 08, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Skin/hair/eye pigmentation 2, red hair/fair skin Other:1

Nov 01, 1995

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

Melanoma Other:1

Dec 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MC1R c.880G>C (p.Asp294His) has been associated with increased risk for melanoma. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (1.64%, Genome Aggregation Database (gnomAD); rs1805009) and is present in ClinVar (ID: 14307). A large meta-analysis has reported an odds ratio of 1.89 [95% CI 4.8-10] for developing melanoma (Williams 2011). In vitro functional studies provide some evidence that the p.Asp294His variant may impact protein function (Beaumont 2007). In summary, this variant is not expected to cause highly penetrant Mendelian disease. p.Asp294His variant is an established risk factor for melanoma.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.8
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.93
MPC		0.13
ClinPred		0.064	T
GERP RS		5.3
Varity_R		0.88
gMVP		0.81
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1805009; hg19: chr16-89986546; COSMIC: COSV59625783; COSMIC: COSV59625783;