ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7942C>G (p.Pro2648Ala) (rs878853547)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478040 SCV000572016 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.7942C>G at the cDNA level, p.Pro2648Ala (P2648A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Pro2648Ala 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 Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Pro2648Ala occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Pro2648Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000804189 SCV000944085 uncertain significance Ataxia-telangiectasia syndrome 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 2648 of the ATM protein (p.Pro2648Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 422523). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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