ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2569C>G (p.Leu857Val) (rs876659486)

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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 RCV000215421 SCV000276017 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-29 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000236914 SCV000293776 uncertain significance not provided 2015-12-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.2569C>G at the cDNA level, p.Leu857Val (L857V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu857Val 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 Leu857Val 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 (Tavtigian 2009, Stracker 2013). 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 Leu857Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000215421 SCV001356365 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing
Invitae RCV001221171 SCV001393197 uncertain significance Ataxia-telangiectasia syndrome 2019-04-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 857 of the ATM protein (p.Leu857Val). 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 conditions. ClinVar contains an entry for this variant (Variation ID: 232001). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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