ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.233C>G (p.Ala78Gly) (rs876659669)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222123 SCV000276374 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-01 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence
GeneDx RCV000235694 SCV000293969 uncertain significance not provided 2016-02-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.233C>G at the cDNA level, p.Ala78Gly (A78G) at the protein level, and results in the change of an Alanine to a Glycine (GCA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala78Gly 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 Alanine and Glycine share similar properties, this is considered a conservative amino acid substitution. ATM Ala78Gly occurs at a position that is conserved in mammals and is not located in a known functional domain (Tavtigian 2009). 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 Ala78Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469622 SCV000546712 uncertain significance Ataxia-telangiectasia syndrome 2016-06-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 78 of the ATM protein (p.Ala78Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. 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. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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