ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3291C>G (p.Phe1097Leu) (rs876658491)

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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 RCV000215026 SCV000273793 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000460107 SCV000546931 uncertain significance Ataxia-telangiectasia syndrome 2017-07-05 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 1097 of the ATM protein (p.Phe1097Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine 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: 230299). 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: "Benign"; Align-GVGD: "Class C15"). 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.
GeneDx RCV000481643 SCV000570191 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.3291C>G at the cDNA level, p.Phe1097Leu (F1097L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Phe1097Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. ATM Phe1097Leu occurs at a position that is conserved across species and is located within the region of interaction with beta-adaptin (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 Phe1097Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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