ClinVar Miner

Submissions for variant NM_000077.5(CDKN2A):c.223C>T (p.Pro75Ser)

dbSNP: rs1202706337
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000798200 SCV000937802 uncertain significance Familial melanoma 2024-07-08 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 proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 75 of the CDKN2A (p16INK4a) protein (p.Pro75Ser). This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is also known as c.266C>T (p.Pro89Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 644311). 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 tolerated. 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 RCV004949919 SCV005559321 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-08 criteria provided, single submitter clinical testing The p.P75S variant (also known as c.223C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 223. The proline at codon 75 is replaced by serine, an amino acid with similar properties. Of note, this alteration is also known as c.266C>T (p.P89L)in the p14(ARF) isoform. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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