ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4379C>T (p.Ala1460Val) (rs376165779)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000777910 SCV000913942 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000478770 SCV000572620 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.4379C>T at the cDNA level, p.Ala1460Val (A1460V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala1460Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Ala1460Val occurs at a position that is conserved 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 Ala1460Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000553522 SCV000622496 uncertain significance Ataxia-telangiectasia syndrome 2018-02-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1460 of the ATM protein (p.Ala1460Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine 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: 423001). 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 tolerated, 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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