ClinVar Miner

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

gnomAD frequency: 0.04832  dbSNP: rs1805007
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Total submissions: 11
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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

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