ClinVar Miner

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

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Total submissions: 6
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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 2020-01-14 criteria provided, single submitter clinical testing The p.R124C variant (also known as c.370C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 370. The arginine at codon 124 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature in multiple melanoma cohorts (Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97(20):1507-15; Orlow I et al. J. Invest. Dermatol., 2007 May;127:1234-43; Capanu M et al. Stat Med, 2008 May;27:1973-92; Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Harland M et al. Hered Cancer Clin Pract. 2014;12(1):20; Burgstaller-Muehlbacher S et al. Melanoma Res., 2015 Oct;25:412-20), but has also been identified in individuals without a personal or family history of melanoma or pancreatic cancer (Ambry Internal Data). This amino acid position is poorly conserved in available vertebrate species, and cystine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000473505 SCV000545516 uncertain significance Hereditary melanoma 2020-10-21 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 C1. 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. 5
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.
Counsyl RCV000663297 SCV000786545 uncertain significance Melanoma-pancreatic cancer syndrome 2018-05-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000215702 SCV000902873 likely benign Hereditary cancer-predisposing syndrome 2016-10-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000478053 SCV001551238 uncertain significance not provided no assertion criteria provided clinical testing The CDKN2A p.R124C variant was identified in multiple individuals with melanoma (Harland_2014_PMID: 25780468; Burgstaller-Muehlbacher_2015_PMID: 26225579; Orlow_2007_PMID: 17218939; Begg_2005_PMID: 16234564). The variant was identified in dbSNP (ID: rs34170727), COSMIC (tissue distribution: skin), and ClinVar (classified as uncertain significance by Counsyl, GeneDx, Ambry Genetics, and Invitae; and as likely benign by Color). The variant was identified in control databases in 30 of 243546 chromosomes at a frequency of 0.0001232, and was observed at the highest frequency in the South Asian population in 22 of 30554 chromosomes (freq: 0.0007200) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R124 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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