ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.95T>C (p.Leu32Pro) (rs878853650)

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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 RCV000561506 SCV000673241 likely pathogenic Hereditary cancer-predisposing syndrome 2016-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification
Integrated Genetics/Laboratory Corporation of America RCV000234305 SCV000917149 pathogenic Hereditary cutaneous melanoma 2018-08-03 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.95T>C (p.Leu32Pro) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 239900 control chromosomes (gnomAD). The variant, c.95T>C, has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Jouenne_2016, Jovanovic_2010, Box_2001, McKenzie_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (McKenzie_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000234305 SCV000283452 likely pathogenic Hereditary cutaneous melanoma 2018-02-02 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 32 of the CDKN2A (p16INK4a) protein (p.Leu32Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in patients and families affected with melanoma and pancreatic cancer (PMID: 19759551, 17218939, 16905682, 20340136, 17047042, 28592523).  It has been shown to segregate with disease in one family (PMID: 8595405). ClinVar contains an entry for this variant (Variation ID: 236992). Experimental studies have shown that this missense change interferes with the interaction between p16INK4a and its binding partners CDK4 and CDK6 (PMID: 20340136). 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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