ClinVar Miner

Submissions for variant NM_000077.5(CDKN2A):c.188T>C (p.Leu63Pro)

dbSNP: rs2131096164
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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 RCV001964531 SCV002127537 uncertain significance Familial melanoma 2023-06-24 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 1367946). This missense change has been observed in individual(s) with melanoma (PMID: 16905682, 17047042). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 63 of the CDKN2A (p16INK4a) protein (p.Leu63Pro).
Ambry Genetics RCV002406961 SCV002722492 pathogenic Hereditary cancer-predisposing syndrome 2022-04-18 criteria provided, single submitter clinical testing The p.L63P pathogenic mutation (also known as c.188T>C), located in coding exon 2 of the CDKN2A gene, results from a T to C substitution at nucleotide position 188. The leucine at codon 63 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a family with more than three patients with melanoma (Goldstein AM et al. J. Med. Genet. 2007 Feb;44:99-106; Harland M et al. Hered. Cancer Clin. Pract. 2014 Nov;12:20). This alteration has been observed in individuals who have a personal or family history that is consistent with CDKN2A-associated disease (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Byeon IJ et al. Mol. Cell 1998 Feb;1(3):421-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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