Submissions for variant NM_002386.4(MC1R):c.496dup (p.Ala166fs)

gnomAD frequency: 0.00002  dbSNP: rs780875127

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000626151	SCV000399961	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 5	2017-04-27	criteria provided, single submitter	clinical testing	The MC1R c.496dupG (p.Ala166GlyfsTer73) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ala166GlyfsTer73 variant has been reported in one study in which it is found in one individual with sporadic malignant melanoma in a heterozygous state (Galore-Haskel et al. 2009). This variant was absent from controls, but is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, however this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of frameshift variants, and the limited evidence in the literature, the p.Ala166GlyfsTer73 variant is classified as a variant of unknown significance, but is suspicious for pathogenicity for malignant melanoma susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626151	SCV000746783	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 5	2017-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000626151	SCV000829196	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 5	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala166Glyfs*73) in the MC1R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acid(s) of the MC1R protein. This variant is present in population databases (rs780875127, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with malignant melanoma (PMID: 19269164). ClinVar contains an entry for this variant (Variation ID: 321429). 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.