ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.250G>T (p.Asp84Tyr) (rs11552822)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000584237 SCV000689596 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000584237 SCV001176643 pathogenic Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing The p.D84Y pathogenic mutation (also known as c.250G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 250. The aspartic acid at codon 84 is replaced by tyrosine, an amino acid with highly dissimilar properties. Functional studies demonstrate that this alteration results in impaired binding with CDK4 and CDK6 (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Ruas M et al. Oncogene 1999 Sep;18(39):5423-34). Further, this alteration occurs at a mutational hotspot, with p.D84N and p.D84H also demonstrating impaired binding (Ruas M et al. Oncogene 1999 Sep;18(39):5423-34). Structural analysis indicates that this alteration dramatically alters the electrostatic character of the CDK-binding surface of p16, resulting in a severe pertubation of the protein structure which likely leads to misfolding and loss of binding (Ruas M et al. Oncogene 1999 Sep;18(39):5423-34; Rajasekaran R et al. Biochimie 2008 Oct;90(10):1523-9; Ambry internal analysis). In addition, this alteration has been reported in multiple families with familial melanoma, including one family with three individuals with cutaneous malignant melanoma and two individuals with dysplastic nevi (Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11; Ruiz A et al. J. Med. Genet. 1999 Jun;36(6):490-3). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001239054 SCV001411899 uncertain significance Hereditary melanoma 2020-09-19 criteria provided, single submitter clinical testing The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. This sequence change replaces aspartic acid with tyrosine at codon 84 of the CDKN2A (p16INK4a) protein (p.Asp84Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. Alternatively, this sequence change replaces arginine with leucine at codon 98 of the CDKN2A (p14ARF) protein (p.Arg98Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with melanoma (PMID: 10874641, 26650189, 26681309, 21462282). ClinVar contains an entry for this variant (Variation ID: 376306). Experimental studies have shown that p.Asp84Tyr in the p16INK4a protein impairs CDK4 and CDK6 binding (PMID: 10498896). In addition, functional studies demonstrate that p.Arg98Leu disrupts CDKN2A (p14ARF) protein function (PMID: 10360174). 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.
Database of Curated Mutations (DoCM) RCV000419046 SCV000505632 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only

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