ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.296G>C (p.Arg99Pro) (rs754806883)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000584101 SCV000689599 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-02 criteria provided, single submitter clinical testing
Invitae RCV000687200 SCV000814754 likely pathogenic Hereditary cutaneous melanoma 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 99 of the CDKN2A (p16INK4a) protein (p.Arg99Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families and individuals affected with melanoma and/or pancreatic cancer (PMID: 9425228, 24660985, 19260062, 21462282, 22841127, 17047042). This variant has also been reported to segregate with disease in at least one of these families (PMID: 19260062). In vitro experimental studies have shown that this missense results in impaired CDK4 and CDK6 binding and disrupted cell cycle regulation and proliferation (PMID: 19260062, 20340316, 2319082). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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