ClinVar Genomic variation as it relates to human health
NM_002386.4(MC1R):c.478C>T (p.Arg160Trp)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1); Benign(1); Likely benign(2)
Pathogenic(1); Uncertain significance(1); Benign(1); Likely benign(2)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002386.4(MC1R):c.478C>T (p.Arg160Trp)
Variation ID: 14310 Accession: VCV000014310.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q24.3 16: 89919736 (GRCh38) [ NCBI UCSC ] 16: 89986144 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 2, 2016 Feb 14, 2024 Feb 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002386.4:c.478C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002377.4:p.Arg160Trp missense NC_000016.10:g.89919736C>T NC_000016.9:g.89986144C>T NG_012026.1:g.6858C>T NG_027810.1:g.2728C>T Q01726:p.Arg160Trp - Protein change
- R160W
- Other names
-
MC1R, ARG160TRP (rs1805008)
- Canonical SPDI
- NC_000016.10:89919735:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.01458 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.01452
1000 Genomes Project 0.01458
Trans-Omics for Precision Medicine (TOPMed) 0.04121
The Genome Aggregation Database (gnomAD), exomes 0.04717
The Genome Aggregation Database (gnomAD) 0.04851
Exome Aggregation Consortium (ExAC) 0.05027
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MC1R | - | - |
GRCh38 GRCh37 |
499 | 559 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| association (1) |
no assertion criteria provided
|
May 1, 2015 | RCV000015381.34 | |
| risk factor (1) |
no assertion criteria provided
|
May 1, 2015 | RCV000015383.30 | |
| Affects (1) |
no assertion criteria provided
|
May 1, 2015 | RCV000015382.29 | |
| Likely benign (1) |
criteria provided, single submitter
|
- | RCV000244718.6 | |
| Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000356300.13 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Mar 23, 2023 | RCV000255906.6 | |
| Likely benign (1) |
no assertion criteria provided
|
- | RCV001281076.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Apr 07, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321870.4
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
The R160W variant in the MC1R gene has been reported numerous times in the homozygous and compound heterozygous state in association with MC1R-related phenotypes including … (more)
The R160W variant in the MC1R gene has been reported numerous times in the homozygous and compound heterozygous state in association with MC1R-related phenotypes including red hair, changes in skin pigmentation, and an increased risk for UV exposure-related melanoma (Smith et al., 1998; Raimondi et al., 2008; Szell et al., 2008; Hoiom et al., 2009). The NHLBI ESP Exome Sequencing Project reports R160W was observed in 7.7% (663/8594) alleles from individuals of European American background. The R160W variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies have shown that the R160W variant reduces cell surface expression of the MC1R protein and results in loss of cAMP signalling (Beaumont et al., 2007; Sanchez-Laorden et al., 2009). We interpret R160W as a risk allele associated with an increased risk for UV exposure-related melanoma. (less)
|
|
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Uncertain significance
(Mar 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224301.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PS3_supporting, PS4_moderate
Number of individuals with the variant: 30
|
|
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Likely benign
(-)
|
criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000308871.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
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Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Melanoma, cutaneous malignant, susceptibility to, 5
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000399959.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
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, … (more)
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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 5
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001727260.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024 |
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552849.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MC1R p.Arg160Trp variant was identified in dbSNP (ID: rs1805008) as “With Pathogenic allele” and in ClinVar as conflicting interpretations of pathogenicity (six submissions: likely … (more)
The MC1R p.Arg160Trp variant was identified in dbSNP (ID: rs1805008) as “With Pathogenic allele” and in ClinVar as conflicting interpretations of pathogenicity (six submissions: likely benign by PreventionGenetics and Illumina Clinical Services Laboratory, pathogenic by GeneDx, and three submissions from OMIM). The associated conditions in ClinVar include: increased analgesia from kappa-opioid receptor agonist, female-specific; skin/hair/eye pigmentation 2, red hair/fair skin; modifier of oculocutaneous albinism, type II; and malignant melanoma susceptibility. The variant was also in Clinvitae and LOVD 3.0 databases. The variant was not identified in COGR, Cosmic, MutDB, and UMD-LSDB databases. The variant was identified in control databases in 12963 of 272086 chromosomes (487 homozygous) at a frequency of 0.047643 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 10040 of 126010 chromosomes (freq: 0.07968), European (Finnish) in 1282 of 19538 chromosomes (freq: 0.06562), Ashkenazi Jewish in 589 of 10256 chromosomes (freq: 0.05743), Other in 298 of 7034 chromosomes (freq: 0.04237), African in 304 of 23942 chromosomes (freq: 0.0127), Latino in 289 of 35298 chromosomes (freq: 0.008187), South Asian in 160 of 30534 chromosomes (freq: 0.00524), and East Asian in 1 of 19474 chromosomes (freq: 0.000051). Raimondi et al. performed a meta-analysis on the association between the most studied MC1R variants, including p.Arg160Trp, and melanoma and/or red hair, fair skin phenotype. The variant was significantly associated with melanoma development, with OR of 1.43 (95 CI) and with red hair and fair skin with OR of 5.0 (95% CI) (Raimondi_2008_18366057). Tagliabue et al. investigated the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC). Data on 3257 NMSC cases and 9391 controls was gathered through the M-SKIP Project (an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics). The variant p.Arg160Trp showed a positive association with NMSC with a summary odds ratio of 1.67 (Tagliabue_2015_26103569). The p.Arg160 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Arg160 residue is conserved across mammals and other organisms, and 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. 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: Raimondi, Sara, et al. "MC1R variants, melanoma and red hair color phenotype: a meta‐analysis." International Journal of Cancer 122.12 (2008): 2753-2760. 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. (less)
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risk factor
(May 01, 2015)
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no assertion criteria provided
Method: literature only
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OCULOCUTANEOUS ALBINISM, TYPE II, MODIFIER OF
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035644.7
First in ClinVar: Apr 04, 2013 Last updated: Nov 11, 2023 |
Comment on evidence:
In an Irish population, Smith et al. (1998) found an association between the arg160-to-trp (R160W) variant of the MC1R gene and red hair and/or fair … (more)
In an Irish population, Smith et al. (1998) found an association between the arg160-to-trp (R160W) variant of the MC1R gene and red hair and/or fair skin (266300). In a study of 24 redheaded individuals (12 male and 12 female) and 24 nonredheaded controls, Mogil et al. (2003) found that 5 women with 2 variant MC1R alleles, all of whom had red hair, displayed significantly greater analgesia from the kappa-opioid pentazocine (613098) than all other groups; 3 of the women were homozygous for R151C (155555.0004) and 2 were compound heterozygous for R151C and R160W (Mogil, 2003). See 155555.0004 and King et al. (2003). In a discovery sample of 2,986 Icelanders and replication samples of 2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found association of the T allele of MC1R SNP rs1805008 (R160W) with red hair (discovery OR = 7.86, P = 4.2 x 10(-95)), with skin sensitivity to sun (discovery OR = 2.30, P = 1.8 x 10(-43)) and with freckling (discovery OR = 2.63, P = 2.8 x 10(-60)). Dong et al. (2014) did not find a significant association between the R160W MC1R variant and Parkinson disease in 2 large datasets of 808 PD patients and 1,623 controls and 5,333 PD patients and 12,019 controls. All the participants were non-Hispanic whites. By sequencing the entire MC1R gene in 870 Spanish patients with Parkinson disease (PD; 168600) and 736 controls, Tell-Marti et al. (2015) found that the R160W MC1R variant was marginally associated with PD (odds ratio of 2.10, p = 0.009, Bonferroni-corrected p = 0.063). The mode of inheritance could not be determined because there were no homozygous carriers, only heterozygous carriers. Lubbe et al. (2016) found no association of the MC1R variant R160W and PD in a cohort of 5,944 PD cases and 4,642 controls collected through the International Parkinson Disease Genomics Consortium (IPDGC). In a reply to Lubbe et al. (2016), Tell-Marti et al. (2016) pointed out that the minor allele frequency (MAF) of the R160W variant in the Spanish population is lower than that found in other European populations, and that different subpopulation stratification in the study of Lubbe et al. (2016) could be limiting the replication of their findings. They also noted discrepancies in the MAF of R160W in Greek control populations in skin cancer and IPDGC studies. Tell-Marti et al. (2016) concluded that attempts to validate their association findings of MC1R and PD be performed in larger and homogenous populations in which control samples specifically not include subjects with cutaneous melanoma or a family history of it, so as to avoid an overrepresentation of risk variants in controls. (less)
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association
(May 01, 2015)
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no assertion criteria provided
Method: literature only
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SKIN/HAIR/EYE PIGMENTATION 2, RED HAIR/FAIR SKIN
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035642.7
First in ClinVar: Apr 04, 2013 Last updated: Nov 11, 2023 |
Comment on evidence:
In an Irish population, Smith et al. (1998) found an association between the arg160-to-trp (R160W) variant of the MC1R gene and red hair and/or fair … (more)
In an Irish population, Smith et al. (1998) found an association between the arg160-to-trp (R160W) variant of the MC1R gene and red hair and/or fair skin (266300). In a study of 24 redheaded individuals (12 male and 12 female) and 24 nonredheaded controls, Mogil et al. (2003) found that 5 women with 2 variant MC1R alleles, all of whom had red hair, displayed significantly greater analgesia from the kappa-opioid pentazocine (613098) than all other groups; 3 of the women were homozygous for R151C (155555.0004) and 2 were compound heterozygous for R151C and R160W (Mogil, 2003). See 155555.0004 and King et al. (2003). In a discovery sample of 2,986 Icelanders and replication samples of 2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found association of the T allele of MC1R SNP rs1805008 (R160W) with red hair (discovery OR = 7.86, P = 4.2 x 10(-95)), with skin sensitivity to sun (discovery OR = 2.30, P = 1.8 x 10(-43)) and with freckling (discovery OR = 2.63, P = 2.8 x 10(-60)). Dong et al. (2014) did not find a significant association between the R160W MC1R variant and Parkinson disease in 2 large datasets of 808 PD patients and 1,623 controls and 5,333 PD patients and 12,019 controls. All the participants were non-Hispanic whites. By sequencing the entire MC1R gene in 870 Spanish patients with Parkinson disease (PD; 168600) and 736 controls, Tell-Marti et al. (2015) found that the R160W MC1R variant was marginally associated with PD (odds ratio of 2.10, p = 0.009, Bonferroni-corrected p = 0.063). The mode of inheritance could not be determined because there were no homozygous carriers, only heterozygous carriers. Lubbe et al. (2016) found no association of the MC1R variant R160W and PD in a cohort of 5,944 PD cases and 4,642 controls collected through the International Parkinson Disease Genomics Consortium (IPDGC). In a reply to Lubbe et al. (2016), Tell-Marti et al. (2016) pointed out that the minor allele frequency (MAF) of the R160W variant in the Spanish population is lower than that found in other European populations, and that different subpopulation stratification in the study of Lubbe et al. (2016) could be limiting the replication of their findings. They also noted discrepancies in the MAF of R160W in Greek control populations in skin cancer and IPDGC studies. Tell-Marti et al. (2016) concluded that attempts to validate their association findings of MC1R and PD be performed in larger and homogenous populations in which control samples specifically not include subjects with cutaneous melanoma or a family history of it, so as to avoid an overrepresentation of risk variants in controls. (less)
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Affects
(May 01, 2015)
|
no assertion criteria provided
Method: literature only
|
INCREASED ANALGESIA FROM KAPPA-OPIOID RECEPTOR AGONIST, FEMALE-SPECIFIC
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035643.7
First in ClinVar: Apr 04, 2013 Last updated: Nov 11, 2023 |
Comment on evidence:
In an Irish population, Smith et al. (1998) found an association between the arg160-to-trp (R160W) variant of the MC1R gene and red hair and/or fair … (more)
In an Irish population, Smith et al. (1998) found an association between the arg160-to-trp (R160W) variant of the MC1R gene and red hair and/or fair skin (266300). In a study of 24 redheaded individuals (12 male and 12 female) and 24 nonredheaded controls, Mogil et al. (2003) found that 5 women with 2 variant MC1R alleles, all of whom had red hair, displayed significantly greater analgesia from the kappa-opioid pentazocine (613098) than all other groups; 3 of the women were homozygous for R151C (155555.0004) and 2 were compound heterozygous for R151C and R160W (Mogil, 2003). See 155555.0004 and King et al. (2003). In a discovery sample of 2,986 Icelanders and replication samples of 2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found association of the T allele of MC1R SNP rs1805008 (R160W) with red hair (discovery OR = 7.86, P = 4.2 x 10(-95)), with skin sensitivity to sun (discovery OR = 2.30, P = 1.8 x 10(-43)) and with freckling (discovery OR = 2.63, P = 2.8 x 10(-60)). Dong et al. (2014) did not find a significant association between the R160W MC1R variant and Parkinson disease in 2 large datasets of 808 PD patients and 1,623 controls and 5,333 PD patients and 12,019 controls. All the participants were non-Hispanic whites. By sequencing the entire MC1R gene in 870 Spanish patients with Parkinson disease (PD; 168600) and 736 controls, Tell-Marti et al. (2015) found that the R160W MC1R variant was marginally associated with PD (odds ratio of 2.10, p = 0.009, Bonferroni-corrected p = 0.063). The mode of inheritance could not be determined because there were no homozygous carriers, only heterozygous carriers. Lubbe et al. (2016) found no association of the MC1R variant R160W and PD in a cohort of 5,944 PD cases and 4,642 controls collected through the International Parkinson Disease Genomics Consortium (IPDGC). In a reply to Lubbe et al. (2016), Tell-Marti et al. (2016) pointed out that the minor allele frequency (MAF) of the R160W variant in the Spanish population is lower than that found in other European populations, and that different subpopulation stratification in the study of Lubbe et al. (2016) could be limiting the replication of their findings. They also noted discrepancies in the MAF of R160W in Greek control populations in skin cancer and IPDGC studies. Tell-Marti et al. (2016) concluded that attempts to validate their association findings of MC1R and PD be performed in larger and homogenous populations in which control samples specifically not include subjects with cutaneous melanoma or a family history of it, so as to avoid an overrepresentation of risk variants in controls. (less)
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Breast Cancer
Affected status: yes
Allele origin:
germline
|
Center of Medical Genetics and Primary Health Care
Accession: SCV001451693.1
First in ClinVar: Jan 09, 2021 Last updated: Jan 09, 2021 |
|
Citation text
Mogil, J. S. Personal Communication. 2003. Montreal, Canada
Citation text
Mogil, J. S. Personal Communication. 2003. Montreal, Canada
Citation text
Mogil, J. S. Personal Communication. 2003. Montreal, Canada
Comment:
The R160W variant in the MC1R gene has been reported numerous times in the homozygous and compound heterozygous state in association with MC1R-related phenotypes including red hair, changes in skin pigmentation, and an increased risk for UV exposure-related melanoma (Smith et al., 1998; Raimondi et al., 2008; Szell et al., 2008; Hoiom et al., 2009). The NHLBI ESP Exome Sequencing Project reports R160W was observed in 7.7% (663/8594) alleles from individuals of European American background. The R160W variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies have shown that the R160W variant reduces cell surface expression of the MC1R protein and results in loss of cAMP signalling (Beaumont et al., 2007; Sanchez-Laorden et al., 2009). We interpret R160W as a risk allele associated with an increased risk for UV exposure-related melanoma.
Comment:
PS3_supporting, PS4_moderate
Comment:
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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
The MC1R p.Arg160Trp variant was identified in dbSNP (ID: rs1805008) as “With Pathogenic allele” and in ClinVar as conflicting interpretations of pathogenicity (six submissions: likely benign by PreventionGenetics and Illumina Clinical Services Laboratory, pathogenic by GeneDx, and three submissions from OMIM). The associated conditions in ClinVar include: increased analgesia from kappa-opioid receptor agonist, female-specific; skin/hair/eye pigmentation 2, red hair/fair skin; modifier of oculocutaneous albinism, type II; and malignant melanoma susceptibility. The variant was also in Clinvitae and LOVD 3.0 databases. The variant was not identified in COGR, Cosmic, MutDB, and UMD-LSDB databases. The variant was identified in control databases in 12963 of 272086 chromosomes (487 homozygous) at a frequency of 0.047643 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 10040 of 126010 chromosomes (freq: 0.07968), European (Finnish) in 1282 of 19538 chromosomes (freq: 0.06562), Ashkenazi Jewish in 589 of 10256 chromosomes (freq: 0.05743), Other in 298 of 7034 chromosomes (freq: 0.04237), African in 304 of 23942 chromosomes (freq: 0.0127), Latino in 289 of 35298 chromosomes (freq: 0.008187), South Asian in 160 of 30534 chromosomes (freq: 0.00524), and East Asian in 1 of 19474 chromosomes (freq: 0.000051). Raimondi et al. performed a meta-analysis on the association between the most studied MC1R variants, including p.Arg160Trp, and melanoma and/or red hair, fair skin phenotype. The variant was significantly associated with melanoma development, with OR of 1.43 (95 CI) and with red hair and fair skin with OR of 5.0 (95% CI) (Raimondi_2008_18366057). Tagliabue et al. investigated the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC). Data on 3257 NMSC cases and 9391 controls was gathered through the M-SKIP Project (an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics). The variant p.Arg160Trp showed a positive association with NMSC with a summary odds ratio of 1.67 (Tagliabue_2015_26103569). The p.Arg160 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Arg160 residue is conserved across mammals and other organisms, and 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. 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: Raimondi, Sara, et al. "MC1R variants, melanoma and red hair color phenotype: a meta‐analysis." International Journal of Cancer 122.12 (2008): 2753-2760. 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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The R160W variant in the MC1R gene has been reported numerous times in the homozygous and compound heterozygous state in association with MC1R-related phenotypes including red hair, changes in skin pigmentation, and an increased risk for UV exposure-related melanoma (Smith et al., 1998; Raimondi et al., 2008; Szell et al., 2008; Hoiom et al., 2009). The NHLBI ESP Exome Sequencing Project reports R160W was observed in 7.7% (663/8594) alleles from individuals of European American background. The R160W variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies have shown that the R160W variant reduces cell surface expression of the MC1R protein and results in loss of cAMP signalling (Beaumont et al., 2007; Sanchez-Laorden et al., 2009). We interpret R160W as a risk allele associated with an increased risk for UV exposure-related melanoma.
Comment:
PS3_supporting, PS4_moderate
Comment:
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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
The MC1R p.Arg160Trp variant was identified in dbSNP (ID: rs1805008) as “With Pathogenic allele” and in ClinVar as conflicting interpretations of pathogenicity (six submissions: likely benign by PreventionGenetics and Illumina Clinical Services Laboratory, pathogenic by GeneDx, and three submissions from OMIM). The associated conditions in ClinVar include: increased analgesia from kappa-opioid receptor agonist, female-specific; skin/hair/eye pigmentation 2, red hair/fair skin; modifier of oculocutaneous albinism, type II; and malignant melanoma susceptibility. The variant was also in Clinvitae and LOVD 3.0 databases. The variant was not identified in COGR, Cosmic, MutDB, and UMD-LSDB databases. The variant was identified in control databases in 12963 of 272086 chromosomes (487 homozygous) at a frequency of 0.047643 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 10040 of 126010 chromosomes (freq: 0.07968), European (Finnish) in 1282 of 19538 chromosomes (freq: 0.06562), Ashkenazi Jewish in 589 of 10256 chromosomes (freq: 0.05743), Other in 298 of 7034 chromosomes (freq: 0.04237), African in 304 of 23942 chromosomes (freq: 0.0127), Latino in 289 of 35298 chromosomes (freq: 0.008187), South Asian in 160 of 30534 chromosomes (freq: 0.00524), and East Asian in 1 of 19474 chromosomes (freq: 0.000051). Raimondi et al. performed a meta-analysis on the association between the most studied MC1R variants, including p.Arg160Trp, and melanoma and/or red hair, fair skin phenotype. The variant was significantly associated with melanoma development, with OR of 1.43 (95 CI) and with red hair and fair skin with OR of 5.0 (95% CI) (Raimondi_2008_18366057). Tagliabue et al. investigated the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC). Data on 3257 NMSC cases and 9391 controls was gathered through the M-SKIP Project (an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics). The variant p.Arg160Trp showed a positive association with NMSC with a summary odds ratio of 1.67 (Tagliabue_2015_26103569). The p.Arg160 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Arg160 residue is conserved across mammals and other organisms, and 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. 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: Raimondi, Sara, et al. "MC1R variants, melanoma and red hair color phenotype: a meta‐analysis." International Journal of Cancer 122.12 (2008): 2753-2760. 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Is the MC1R variant p.R160W associated with Parkinson's? | Lubbe SJ | Annals of neurology | 2016 | PMID: 26389967 |
| Reply. | Tell-Martí G | Annals of neurology | 2016 | PMID: 26389780 |
| The MC1R melanoma risk variant p.R160W is associated with Parkinson disease. | Tell-Marti G | Annals of neurology | 2015 | PMID: 25631192 |
| Susceptibility loci for pigmentation and melanoma in relation to Parkinson's disease. | Dong J | Neurobiology of aging | 2014 | PMID: 24439955 |
| Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients. | Council ML | Experimental dermatology | 2009 | PMID: 19320745 |
| MC1R variants, melanoma and red hair color phenotype: a meta-analysis. | Raimondi S | International journal of cancer | 2008 | PMID: 18366057 |
| Genetic determinants of hair, eye and skin pigmentation in Europeans. | Sulem P | Nature genetics | 2007 | PMID: 17952075 |
| Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. | Beaumont KA | Human molecular genetics | 2007 | PMID: 17616515 |
| Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. | Mogil JS | Journal of medical genetics | 2005 | PMID: 15994880 |
| MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). | King RA | American journal of human genetics | 2003 | PMID: 12876664 |
| Melanocortin 1 receptor variants in an Irish population. | Smith R | The Journal of investigative dermatology | 1998 | PMID: 9665397 |
| Mogil, J. S. Personal Communication. 2003. Montreal, Canada | - | - | - | - |
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Text-mined citations for rs1805008 ...
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Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.