ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8656G>A (p.Val2886Ile) (rs1064795066)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483866 SCV000570509 uncertain significance not provided 2016-05-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.8656G>A at the cDNA level, p.Val2886Ile (V2886I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Val2886Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Val2886Ile occurs at a position that is conserved across species and is located within the PI3-PI4 kinase domain and the p53 interaction domain (Tavtigian 2009, Stracker 2013, UniProt). 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 Val2886Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000704042 SCV000832975 uncertain significance Ataxia-telangiectasia syndrome 2018-02-14 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2886 of the ATM protein (p.Val2886Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. 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: 421335). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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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