16-89919342-CA-CAA

Position:

chr16-89919342-CA-CAA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2

The NM_002386.4(MC1R):c.86dup(p.Asn29LysfsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.00333 in 1,612,934 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 15 hom. )

Consequence

MC1R
NM_002386.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.74

Variant links:

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]

MC1R links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

BS2

High AC in GnomAd4 at 312 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4 linkuse as main transcript	c.86dup	p.Asn29LysfsTer14	frameshift_variant	1/1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MC1R	ENST00000555147.2 linkuse as main transcript	c.86dup	p.Asn29LysfsTer14	frameshift_variant	1/1		NM_002386.4	ENSP00000451605	P1
MC1R	ENST00000555427.1 linkuse as main transcript	c.86dup	p.Asn29LysfsTer14	frameshift_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1 linkuse as main transcript	c.86dup	p.Asn29LysfsTer14	frameshift_variant	3/3	5		ENSP00000492011	P1

Frequencies

GnomAD3 genomes

AF:

0.00205

AC:

312

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00385

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00199

AC:

489

AN:

245964

Hom.:

AF XY:

0.00205

AC XY:

275

AN XY:

134180

show subpopulations

Gnomad AFR exome

AF:

0.000530

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000420

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.00346

AC:

5061

AN:

1460614

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

2482

AN XY:

726578

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000361

Gnomad4 NFE exome

AF:

0.00439

Gnomad4 OTH exome

AF:

0.00217

GnomAD4 genome

AF:

0.00205

AC:

312

AN:

152320

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

121

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00385

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00285

Hom.:

Bravo

AF:

0.00219

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00386

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Melanoma, cutaneous malignant, susceptibility to, 5

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The MC1R c.86dupA (p.Asn29LysfsTer14) variant has been reported in at least three studies and is found in one patient in a homozygous state, one in a compound heterozygous state, and four in a heterozygous state. A majority of these patients also carried variants in the CDKN2A gene, which is also associated with malignant melanoma susceptibility (Goldstein et al. 2005; Guan et al. 2013; Mangas et al. 2016). The p.Asn29LysfsTer14 variant was also present in nine unaffected individuals in a heterozygous state (Goldstein et al. 2005). In addition, this variant was detected in a compound heterozygous state in an individual with red hair, but affected status was not specified (Flanagan et al. 2000). The p.Asn29LysfsTer14 variant was detected in one of 2358 control chromosomes (Guan et al. 2013; Mangas et al. 2016) and is reported at a frequency of 0.00433 in the European American population of the Exome Sequencing Project. Due to the potential impact of stop-gained variants, the p.Asn29LysfsTer14 variant is classified as a variant of unknown significance but suspicious for pathogenicity for malignant melanoma susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Asn29Lysfs*14) in the MC1R gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MC1R cause disease. This variant is present in population databases (rs312262906, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 15221796, 16567973, 24982914). ClinVar contains an entry for this variant (Variation ID: 239162). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over