ClinVar Miner

Submissions for variant NM_002386.4(MC1R):c.917G>A (p.Arg306His)

gnomAD frequency: 0.00016  dbSNP: rs368507952
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000559368 SCV000648560 uncertain significance Melanoma, cutaneous malignant, susceptibility to, 5 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 306 of the MC1R protein (p.Arg306His). This variant is present in population databases (rs368507952, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 16982779, 19269164, 23312576, 23360207, 24982914). It has also been observed to segregate with oculocutaneous albinism in a single family (PMID: 23312576), but the clinical significance of this finding is uncertain. ClinVar contains an entry for this variant (Variation ID: 470716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MC1R protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina RCV000559368 SCV001275784 benign Melanoma, cutaneous malignant, susceptibility to, 5 2017-09-08 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
3billion RCV002250656 SCV002521489 uncertain significance Tyrosinase-positive oculocutaneous albinism 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%) but quite commonly in the south asian population (0.1%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MC1R- related disorder (PMID: 16645598). However, the evidence of pathogenicity is insufficient at this time and there are conflicting interpretations of pathogenicity (Clinvar ID: VCV000470716). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.

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