ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.339G>A (p.Leu113=) (rs575031539)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132098 SCV000187162 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-08 criteria provided, single submitter clinical testing ​The p.A128T variant (also known as c.382G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 382 of the p14 protein-encoding isoform. The alanine at codon 128 is replaced by threonine, an amino acid with similar properties. This alteration does not result in an amino acid change in the major, p16 transcript of CDKN2A. This alteration has been identified in one family with melanoma (FitzGerald MG et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Aug;93:8541-5). This amino acid position is not well conserved in available 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.
GeneDx RCV000478157 SCV000569855 uncertain significance not provided 2016-04-04 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.382G>A at the cDNA level, p.Ala128Thr (A128T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC) in exon 2 of the p14-ARF protein. The CDKN2A gene encodes the p16 protein, and using an alternate reading frame, the p14-ARF protein as well. Of note, this variant also results in a change to the p16 protein; however, that amino acid substitution is silent (p.Leu113Leu). This variant was observed in individuals with personal and/or family histories of melanoma (FitzGerald 1996, Goldstein 2007). CDKN2A Ala128Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A Ala128Thr occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CDKN2A Ala128Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000638964 SCV000760521 uncertain significance Hereditary melanoma 2020-09-24 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 alanine with threonine at codon 128 of the CDKN2A (p14ARF) protein (p.Ala128Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. Alternatively, this sequence change affects codon 113 of the CDKN2A (p16INK4a) mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDKN2A (p16INK4a) protein (p.Leu113Leu). This variant is present in population databases (rs575031539, ExAC 0.002%). This variant has been reported in the literature in a family with melanoma (PMID: 8710906). ClinVar contains an entry for this variant (Variation ID: 142725). A different change, c.382G>C and c.383C>T on the same chromosome, giving rise to a different protein effect p.Ala128Leu, also known as [p.Leu113Leu;p.Pro114Ser] on p16INK4a, has been reported in multiple families and individuals with melanoma (PMID: 16905682, 17492760, 17047042, 19260062, 26775776). The clinical significance of p.Ala128Leu is uncertain. In the literature, this has been erroneously referred to the same protein effect p.Ala128Thr as this variant (PMID: 17047042, 16905682). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Color Health, Inc RCV000132098 SCV000903859 likely benign Hereditary cancer-predisposing syndrome 2016-11-07 criteria provided, single submitter clinical testing

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