ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8032G>A (p.Gly2678Arg) (rs766730487)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567730 SCV000667832 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000567730 SCV000911429 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
GeneDx RCV000484889 SCV000566788 uncertain significance not provided 2015-06-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.8032G>A at the cDNA level, p.Gly2678Arg (G2678R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Gly2678Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Gly2678Arg occurs at a position that is not conserved, with Arginine being the naturally occurring amino acid at this position in two species, and is not located in a known functional domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Gly2678Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000557756 SCV000622798 uncertain significance Ataxia-telangiectasia syndrome 2018-07-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2678 of the ATM protein (p.Gly2678Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs766730487, ExAC 0.003%) but 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare 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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