ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.247C>T (p.His83Tyr) (rs121913385)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000638983 SCV000760541 uncertain significance Hereditary cutaneous melanoma 2018-06-17 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 histidine with tyrosine at codon 83 of the CDKN2A (p16INK4a) protein (p.His83Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. Alternatively, this sequence change replaces alanine with valine at codon 97 of the CDKN2A (p14ARF) protein (p.Ala97Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with sporadic and multiple primary melanomas (PMID: 16234564, 21462282, 16896043). ClinVar contains an entry for this variant (Variation ID: 376307). Experimental studies have shown that p.His83Tyr in p16INK4a reduces protein expression and causes inability to inhibit cell growth and cell cycle arrest (PMID: 7780957, 8521414, 9324288, 10491434). The functional significance p.Ala97Val in p14ARF has not been tested. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
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 Adenocarcinoma of stomach 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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