ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.251A>C (p.Asp84Ala) (rs587782792)

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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 RCV000132342 SCV000187431 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient evidence,Structural Evidence
GeneDx RCV000236474 SCV000292885 likely pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.251A>C at the cDNA level, p.Asp84Ala (D84A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAC>GCC) in exon 2. This variant was observed in at least four individuals with a personal history of melanoma, at least one of whom also had a family history of melanoma and/or pancreatic cancer (Orlow 2001, Niendorf 2006, Demenais 2010, Harland 2014). This residue has been suggested to be important for binding to CDK6 (Ruas 1999). CDKN2A Asp84Ala was not observed in large population cohorts (Lek 2016). Since Aspartic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A Asp84Ala occurs at a position that is conserved across species and is located in the ANK 3 repeat domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. In addition, this variant has been observed in multiple families with personal and family histories of melanoma and pancreatic cancer at this laboratory. Based on currently available evidence, we consider CDKN2A Asp84Ala to be a likely pathogenic variant.
Invitae RCV000687345 SCV000814908 uncertain significance Hereditary cutaneous melanoma 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 84 of the CDKN2A (p16INK4a) protein (p.Asp84Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with melanoma (PMID: 11687599, 15761864, 16169933, 20876876, 21462282). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 142882). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, 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.
PreventionGenetics RCV000236474 SCV000805823 uncertain significance not provided 2017-11-09 criteria provided, single submitter clinical testing

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