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 Lines of evidence used in support of classification: Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Color RCV000494450 SCV000910774 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-15 criteria provided, single submitter clinical testing
Invitae RCV000638989 SCV000760547 uncertain significance Hereditary cutaneous melanoma 2017-12-08 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.

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