ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.45G>T (p.Trp15Cys) (rs138677674)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766725 SCV000210953 uncertain significance not provided 2014-10-09 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.45G>T at the cDNA level, p.Trp15Cys (W15C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDKN2A Trp15Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tryptophan and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A Trp15Cys occurs at a position that is variable across species and is located in the first Ankyrin repeat domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether CDKN2A Trp15Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160420 SCV000601033 uncertain significance not specified 2017-03-23 criteria provided, single submitter clinical testing
Invitae RCV000695173 SCV000823656 likely benign Hereditary melanoma 2019-10-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV001525822 SCV001736017 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-08 criteria provided, single submitter clinical testing This missense variant replaces tryptophan with cysteine at codon 15 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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