16-89919709-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002386.4(MC1R):c.451C>T(p.Arg151Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0749 in 1,606,188 control chromosomes in the GnomAD database, including 5,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (229 hom., cov: 33)
  • Exomes 𝑓: 0.078 (5550 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:3
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007609129).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.451C>T	p.Arg151Cys	missense_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.451C>T	p.Arg151Cys	missense_variant	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1	c.451C>T	p.Arg151Cys	missense_variant	3/4	5
MC1R	ENST00000639847.1	c.451C>T	p.Arg151Cys	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7044 AN: 152234 Hom.: 229 Cov.: 33

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0746

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0741

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0442 AC: 10719 AN: 242744 Hom.: 427 AF XY: 0.0447 AC XY: 5902 AN XY: 132162

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.00937

Gnomad ASJ exome AF: 0.0656

Gnomad EAS exome AF: 0.000613

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.0705

Gnomad NFE exome AF: 0.0718

Gnomad OTH exome AF: 0.0412

GnomAD4 exome AF: 0.0779 AC: 113202 AN: 1453836 Hom.: 5550 Cov.: 35 AF XY: 0.0754 AC XY: 54534 AN XY: 723648

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0677

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.00400

Gnomad4 FIN exome AF: 0.0665

Gnomad4 NFE exome AF: 0.0928

Gnomad4 OTH exome AF: 0.0643

GnomAD4 genome AF: 0.0462 AC: 7045 AN: 152352 Hom.: 229 Cov.: 33 AF XY: 0.0444 AC XY: 3304 AN XY: 74492

Gnomad4 AFR AF: 0.0148

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0746

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.0699

Gnomad4 NFE AF: 0.0741

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0658 Hom.: 302

Bravo AF: 0.0434

TwinsUK AF: 0.0995 AC: 369

ALSPAC AF: 0.0900 AC: 347

ESP6500AA AF: 0.0171 AC: 75

ESP6500EA AF: 0.0762 AC: 655

ExAC AF: 0.0446 AC: 5409

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MC1R p.(Arg151Cys) variant was not identified in the Cosmic or MutDB databases however it was identified in dbSNP (ID: rs1805007) as we all as ClinVar (reported as benign by Prevention Genetics and by Invitae for Cutaneous malignant melanoma 5, reported as pathogenic by GeneDx and reported as likely benign by Illumina for Malignant Melanoma Susceptibility), Clinvitae and LOVD 3.0. The variant was identified in control databases in 12284 of 274116 chromosomes (466 homozygous) at a frequency of 0.044813 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 9141 of 127252 chromosomes (freq: 0.07183), European (Finnish) in 1376 of 19504 chromosomes (freq: 0.07055), Ashkenazi Jewish in 670 of 10300 chromosomes (freq: 0.06505), other in 302 of 7104 chromosomes (freq: 0.04251), African in 333 of 24564 chromosomes (freq: 0.01356), Latino in 338 of 35330 chromosomes (freq: 0.009567), South Asian in 111 of 30564 chromosomes (freq: 0.003632) and East Asian in 13 of 19498 chromosomes (freq: 0.000667). This variant has been found through genome wide association studies to be associated with an increased risk of skin cancer (Tagliabue_2015_26103569). The p.Arg151 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the R variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. References: Tagliabue, Elena, et al. "MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project." British journal of cancer 113.2 (2015): 354. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	Published functional studies demonstrate a dominant negative effect on expression, which results in a decrease in the receptor's ability to elevate intracellular cAMP levels and a complete loss of receptor function at the cell surface (Beaumont et al., 2007; Sanchez-Laorden et al., 2009); This variant is associated with the following publications: (PMID: 23392294, 19799798, 19452503, 19924138, 10403794, 24665948, 23522749, 19269164, 24660985, 11875032, 24081230, 18366057, 22572819, 20876876, 19656326, 17616515, 9571181, 9302268, 11179997, 26103569, 27251790, 23647022, 24335900, 30531825, 31382929, 30414346, 14709592, 27924526, 11500805, 11500806) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 21, 2022	PS3_supporting, PS4_moderate -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

OCULOCUTANEOUS ALBINISM, TYPE II, MODIFIER OF Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2015

- -

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

association, no assertion criteria provided

literature only

OMIM

May 01, 2015

- -

Increased analgesia from kappa-opioid receptor agonist, female-specific Other:1

Affects, no assertion criteria provided

literature only

OMIM

May 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;.;T;T
MetaRNN	Benign	0.0076	T;T;T;T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Pathogenic	-7.4	D;.;D;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.013	D;.;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.72
MPC		0.13
ClinPred		0.090	T
GERP RS		4.8
Varity_R		0.76
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805007; hg19: chr16-89986117;