ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460994 SCV000545514 uncertain significance Hereditary melanoma 2020-07-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 68 of the CDKN2A (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 observed in individuals with melanoma, pancreatic cancer, vocal cord cancer, and basal cell carcinoma (PMID: 8710906, 11075991, 21462282). ClinVar contains an entry for this variant (Variation ID: 406701). 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 and their clinical significance is uncertain. This variant disrupts the p.Ala68 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425228, 18983535, 25780468, 21462282, 11518711, 19260062, 20340136). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics RCV000519825 SCV000622113 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-29 criteria provided, single submitter clinical testing The p.A68V variant (also known as c.203C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 203. The alanine at codon 68 is replaced by valine, an amino acid with similar properties. This alteration does not result in an amino-acid change in the p14-encoding isoform of CDKN2A. This alteration has been detected in several melanoma-affected kindreds as well as an individual affected with pancreatic cancer (among other cancers); although it did not completely segregate with disease (FitzGerald MG et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Aug;93:8541-5; Gerdes B et al. Pancreas, 2000 Nov;21:369-75; Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11; Potjer TP et al. J. Med. Genet., 2018 10;55:661-668; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Internal analysis shows that this amino acid position lies within a structural hotspot where many pathogenic mutations are found and it is likely to affect binding to CDK4 (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000519825 SCV001360048 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-04 criteria provided, single submitter clinical testing

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