ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.67G>T (p.Gly23Cys) (rs1131691186)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000494450 SCV000581509 likely pathogenic Hereditary cancer-predisposing syndrome 2016-06-15 criteria provided, single submitter clinical testing The p.G23C variant (also known as c.67G>T), located in coding exon 1 of the CDKN2A gene, results from a G to T substitution at nucleotide position 67. The glycine at codon 23 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in multiple individuals with personal and family histories of melanoma (Blackwood MA et al. Cancer 2002 Apr; 94(8):2248-55; Ambry internal data). This variant is predicted to be likely deleterious using a combination of in silico analyses and results of a proliferation assay consistent with loss of protein function (Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). In addition, structural analysis predicts that the p.G23C variant results in severe perturbation of the protein, likely resulting in misfolding and loss of binding (Ambry internal data). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5737 samples (11474 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 75000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000638989 SCV000760547 uncertain significance Hereditary melanoma 2020-05-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 23 of the CDKN2A (p16INK4a) protein (p.Gly23Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with melanoma (PMID: 12001124, 21462282). ClinVar contains an entry for this variant (Variation ID: 429109). Experimental studies have shown that this missense change leads to increased cellular proliferation, indicating p16INK4a loss of function (PMID: 24659262). Different missense substitutions at this codon (p.Gly23Asp, Gly23Ser) have been determined to be likely pathogenic (PMID: 21462282, 19260062, 9425228, 20340136, 19712690, 17992122, 24659262). This suggests that the glycine residue is critical for CDKN2A (p16INK4a) protein function and that other missense substitutions at this position may also be pathogenic. 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.
Color Health, Inc RCV000494450 SCV000910774 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-15 criteria provided, single submitter clinical testing

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