ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1741T>G (p.Leu581Val) (rs876659822)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219147 SCV000276688 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000219147 SCV000681995 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing
GeneDx RCV000484735 SCV000572430 uncertain significance not provided 2016-12-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.1741T>G at the cDNA level, p.Leu581Val (L581V) at the protein level, and results in the change of a Leucine to a Valine (TTA>GTA). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a somatic variant in a head and neck squamous cell carcinoma cell line (Nichols 2014). ATM Leu581Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. ATM Leu581Val occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Leu581Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000627927 SCV000748812 uncertain significance Ataxia-telangiectasia syndrome 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 581 of the ATM protein (p.Leu581Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. 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: 232530). 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, 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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