Submissions for variant NM_002386.4(MC1R):c.451C>T (p.Arg151Cys)

gnomAD frequency: 0.04832  dbSNP: rs1805007

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000242808	SCV000308868	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000255991	SCV000321867	benign	not provided	2018-01-04	criteria provided, single submitter	clinical testing	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)
Illumina Laboratory Services, Illumina	RCV000472249	SCV000399954	benign	Melanoma, cutaneous malignant, susceptibility to, 5	2018-03-06	criteria provided, single submitter	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.
Invitae	RCV000472249	SCV000556936	benign	Melanoma, cutaneous malignant, susceptibility to, 5	2024-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000255991	SCV004224300	uncertain significance	not provided	2022-07-21	criteria provided, single submitter	clinical testing	PS3_supporting, PS4_moderate
OMIM	RCV000015385	SCV000035646	association	Skin/hair/eye pigmentation 2, red hair/fair skin	2015-05-01	no assertion criteria provided	literature only
OMIM	RCV000015386	SCV000035647	affects	Increased analgesia from kappa-opioid receptor agonist, female-specific	2015-05-01	no assertion criteria provided	literature only
OMIM	RCV000015387	SCV000035648	risk factor	OCULOCUTANEOUS ALBINISM, TYPE II, MODIFIER OF	2015-05-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000255991	SCV001553820	likely benign	not provided		no assertion criteria provided	clinical testing	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.
Clinical Genetics, Academic Medical Center	RCV000242808	SCV002034604	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000255991	SCV002035337	likely benign	not provided		no assertion criteria provided	clinical testing