ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.203C>T (p.Ala68Val) (rs1060501260)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000519825 SCV000622113 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-08 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
Invitae RCV000460994 SCV000545514 uncertain significance Hereditary cutaneous melanoma 2017-10-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 68 of the p16INK4a protein (p.Ala68Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with melanoma, although the brother of this individual who also had melanoma did not carry the variant (PMID: 8710906). It was also observed in an individual with pancreatic cancer, who had vocal cord cancer and basal cell carcinoma 4 years prior (PMID: 11075991). In a third study, this variant was seen in a family with melanoma, as well as in a non-affected carrier (PMID: 21462282). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Ala68Leu) has been reported in individuals affected with cutaneous melanoma, and segregated with disease in one family (PMID: 9425228, 18983535, 25780468). In addition, experimental studies have shown that p.Ala68Leu causes disruption of the p16INK4a protein function (PMID: 21462282, 11518711, 19260062, 20340136). This suggests that the alanine residue is critical for CDKN2A (p16INK4a) protein function and that other missense substitutions at this position may also be damaging. 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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