Submissions for variant NM_002386.4(MC1R):c.478C>T (p.Arg160Trp)

gnomAD frequency: 0.04851  dbSNP: rs1805008

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000244718	SCV000308871	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000255906	SCV000321870	pathogenic	not provided	2016-04-07	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000356300	SCV000399959	likely benign	Melanoma, cutaneous malignant, susceptibility to, 5	2017-04-27	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000356300	SCV001727260	benign	Melanoma, cutaneous malignant, susceptibility to, 5	2024-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000255906	SCV004224301	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	PS3_supporting, PS4_moderate
OMIM	RCV000015381	SCV000035642	association	Skin/hair/eye pigmentation 2, red hair/fair skin	2015-05-01	no assertion criteria provided	literature only
OMIM	RCV000015382	SCV000035643	affects	Increased analgesia from kappa-opioid receptor agonist, female-specific	2015-05-01	no assertion criteria provided	literature only
OMIM	RCV000015383	SCV000035644	risk factor	OCULOCUTANEOUS ALBINISM, TYPE II, MODIFIER OF	2015-05-01	no assertion criteria provided	literature only
Center of Medical Genetics and Primary Health Care	RCV001281076	SCV001451693	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000255906	SCV001552849	likely benign	not provided		no assertion criteria provided	clinical testing	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.