Submissions for variant NM_002386.4(MC1R):c.880G>C (p.Asp294His)

gnomAD frequency: 0.01121  dbSNP: rs1805009

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080639	SCV000287390	benign	Melanoma, cutaneous malignant, susceptibility to, 5	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000347221	SCV000329659	benign	not provided	2018-01-04	criteria provided, single submitter	clinical testing	Considered a low risk allele, case control studies suggest this variant is associated with early onset cutaneous melanoma (Cust et al., 2012); Reported in association with red hair, fair skin, increased risk for melanoma, increased risk of photoaging and congenital melanocytic nevi (Puig-Butille et al., 2013; Kinsler et al., 2012; Ibarrola-Villava et al., 2014); Functional characterization of the variant show decreased ability to stimulate cAMP production, and altered cell surface expression (Schioth et al., 1999; Sanchez-Laorden et al., 2009); Observed in 920/66568 (1.4%) alleles from individuals of European background, including 6 unrelated homozygous individuals in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22464597, 12789280, 26103569, 26197705, 10403794, 24665948, 19799798, 24660985, 11875032, 17616515, 18366057, 19452503, 22572819, 24335900, 19656326, 7581459, 23647022, 22095472, 9302268, 11179997, 30531825, 31382929, 30414346, 14709592, 11500805)
Illumina Laboratory Services, Illumina	RCV001080639	SCV000399975	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195217	SCV001365524	risk factor	Melanoma	2019-12-04	criteria provided, single submitter	clinical testing	MC1R c.880G>C (p.Asp294His) has been associated with increased risk for melanoma. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (1.64%, Genome Aggregation Database (gnomAD); rs1805009) and is present in ClinVar (ID: 14307). A large meta-analysis has reported an odds ratio of 1.89 [95% CI 4.8-10] for developing melanoma (Williams 2011). In vitro functional studies provide some evidence that the p.Asp294His variant may impact protein function (Beaumont 2007). In summary, this variant is not expected to cause highly penetrant Mendelian disease. p.Asp294His variant is an established risk factor for melanoma.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000347221	SCV003799321	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000347221	SCV004224302	uncertain significance	not provided	2022-03-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000347221	SCV005215896	likely benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000015377	SCV000035638	association	Skin/hair/eye pigmentation 2, red hair/fair skin	1995-11-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003891437	SCV000308874	likely benign	MC1R-related disorder	2021-04-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Yale Center for Mendelian Genomics, Yale University	RCV000662303	SCV000784631	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2015-09-22	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000851264	SCV000993520	likely pathogenic	Skin and Hair Hypopigmentation	2015-09-22	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000347221	SCV001554278	likely benign	not provided		no assertion criteria provided	clinical testing	The MC1R p.Asp294His variant has been reported in the literature multiple times in association with melanoma development, red hair and fair skin (Raimondi_2008_PMID:18366057; Zorina-Lichtenwalter_2019_PMID:30657907). The variant was identified in dbSNP (ID: rs1805009), LOVD 3.0 and ClinVar (classified as benign by Invitae, as likely benign by Prevention Genetics and Illumina, as likely pathogenic by Yale Center for Mendelian Genomics and University of Washington Center for Mendelian Genomics, and as pathogenic by GeneDx). The variant was identified in control databases in 2568 of 280442 chromosomes (23 homozygous) at a frequency of 0.009157 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2082 of 128324 chromosomes (freq: 0.01622), Other in 78 of 7136 chromosomes (freq: 0.01093), Latino in 256 of 35366 chromosomes (freq: 0.007239), African in 82 of 24150 chromosomes (freq: 0.003395), European (Finnish) in 53 of 24992 chromosomes (freq: 0.002121) and Ashkenazi Jewish in 17 of 10346 chromosomes (freq: 0.001643), but was not observed in the East Asian or South Asian populations. The p.D294H variant was found to have a dominant negative effect on MC1R cAMP signialling but had normal cell surface expression (Beaumont_2007_PMID:17616515). The p.Asp294 residue is conserved across mammals and other organisms, and four out of five 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.