ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7531A>T (p.Ile2511Phe) (rs146069748)

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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 RCV000132099 SCV000187164 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000236905 SCV000293212 uncertain significance not provided 2015-10-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.7531A>T at the cDNA level, p.Ile2511Phe (I2511F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATT>TTT). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. ATM Ile2511Phe was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. ATM Ile2511Phe occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013, UniProt). 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 Ile2511Phe is pathogenic or benign.
Invitae RCV000196793 SCV000254146 uncertain significance Ataxia-telangiectasia syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 2511 of the ATM protein (p.Ile2511Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs146069748, ExAC 0.01%) but has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142726). 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: "Deleterious"; 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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