ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5237G>T (p.Gly1746Val) (rs879254135)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235883 SCV000293608 uncertain significance not provided 2015-12-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.5237G>T at the cDNA level, p.Gly1746Val (G1746V) at the protein level, and results in the change of a Glycine to a Valine (GGA>GTA) in exon 35. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Gly1746Val 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 Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Gly1746Val occurs at a position that is conserved across species and is not located in a known functional domain (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 Gly1746Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000470344 SCV000547027 uncertain significance Ataxia-telangiectasia syndrome 2018-06-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 1746 of the ATM protein (p.Gly1746Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with progressive cerebellar atrophy and ataxia (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 246169). 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 C0"). 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.
Ambry Genetics RCV000569852 SCV000660539 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-26 criteria provided, single submitter clinical testing

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