ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8596C>T (p.Leu2866Phe) (rs368666328)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217814 SCV000274976 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-06 criteria provided, single submitter clinical testing
GeneDx RCV000236111 SCV000293514 uncertain significance not provided 2015-11-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.8596C>T at the cDNA level, p.Leu2866Phe (L2866F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu2866Phe 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 Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. ATM Leu2866Phe occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within PI3K/PI4K domain and region of interaction with TP53 (Tavtigian 2009). 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 Leu2866Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000465062 SCV000546717 uncertain significance Ataxia-telangiectasia syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 2866 of the ATM protein (p.Leu2866Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 231206). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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