ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2723T>C (p.Val908Ala) (rs754738085)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000581765 SCV000687413 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-17 criteria provided, single submitter clinical testing
GeneDx RCV000235339 SCV000294077 uncertain significance not provided 2016-03-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.2723T>C at the cDNA level, p.Val908Ala (V908A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Val908Ala 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 Alanine share similar properties, this is considered a conservative amino acid substitution. ATM Val908Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Val908Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000554420 SCV000622353 uncertain significance Ataxia-telangiectasia syndrome 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 908 of the ATM protein (p.Val908Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. 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: 246496). 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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