ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.370C>T (p.Arg124Cys) (rs34170727)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215702 SCV000275190 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215702 SCV000902873 likely benign Hereditary cancer-predisposing syndrome 2016-10-24 criteria provided, single submitter clinical testing
Counsyl RCV000663297 SCV000786545 uncertain significance Melanoma-pancreatic cancer syndrome 2018-05-25 criteria provided, single submitter clinical testing
GeneDx RCV000478053 SCV000568687 uncertain significance not provided 2018-08-07 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.370C>T at the cDNA level, p.Arg124Cys (R124C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been observed in multiple individuals with a single primary melanoma and one individual with a family history of melanoma (Begg 2005, Capanu 2008, Miller 2011, Harland 2014, Burgstaller-Muehlbacher 2015). CDKN2A Arg124Cys was observed at an allele frequency of 0.07% (21/30750) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the ANK4 repeat region (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDKN2A Arg124Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473505 SCV000545516 uncertain significance Hereditary cutaneous melanoma 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 124 of the CDKN2A (p16INK4a) protein (p.Arg124Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs34170727, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with melanoma (PMID: 16234564, 21462282, 25780468, 17218939, 26225579). ClinVar contains an entry for this variant (Variation ID: 231362). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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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