ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7553C>T (p.Pro2518Leu) (rs879254136)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236198 SCV000293609 uncertain significance not provided 2015-11-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.7553C>T at the cDNA level, p.Pro2518Leu (P2518L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Pro2518Leu 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 Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Pro2518Leu occurs at a position that is conserved in mammals and is located within the FAT domain (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 Pro2518Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000474629 SCV000546807 uncertain significance Ataxia-telangiectasia syndrome 2016-11-09 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2518 of the ATM protein (p.Pro2518Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 246170). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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