ClinVar Miner

Submissions for variant NM_000077.5(CDKN2A):c.247C>T (p.His83Tyr)

dbSNP: rs121913385
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000638983 SCV000760541 uncertain significance Familial melanoma 2023-11-24 criteria provided, single submitter clinical testing The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 83 of the CDKN2A (p16INK4a) protein (p.His83Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sporadic and multiple primary melanomas (PMID: 16234564, 16896043, 21462282). This variant is also known as c.290C>T (p.Ala97Val) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 376307). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 7780957, 8521414, 9324288, 10491434). 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 RCV002446641 SCV002735394 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-11 criteria provided, single submitter clinical testing The p.H83Y variant (also known as c.247C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 247. The histidine at codon 83 is replaced by tyrosine, an amino acid with similar properties. This alteration was identified in cohorts with sporadic and multiple melanomas (Begg CB et al. J Natl Cancer Inst, 2005 Oct;97:1507-15; Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). Protein functional studies have shown this variant to have inhibited CDK4 and CDK6 binding and to have increased proliferation activity compared to wild-type (Yang R et al. Cancer Res, 1995 Jun;55:2503-6; Gombart AF et al. Leukemia, 1997 Oct;11:1673-80; Yarbrough WG et al. J Natl Cancer Inst, 1999 Sep;91:1569-74). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc. RCV003316521 SCV004020160 likely pathogenic Melanoma-pancreatic cancer syndrome 2023-03-08 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 35001868, 9324288]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21462282, 16234564].
Baylor Genetics RCV003476006 SCV004212517 uncertain significance Melanoma and neural system tumor syndrome 2023-05-26 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000426295 SCV000505633 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439424 SCV000505866 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419112 SCV000505867 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429387 SCV000505868 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438754 SCV000505869 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421013 SCV000505870 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432117 SCV000505871 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438919 SCV000505872 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423848 SCV000505873 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only

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