ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7736G>C (p.Arg2579Thr) (rs879254206)

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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 RCV000569511 SCV000660513 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000236150 SCV000293832 uncertain significance not provided 2016-01-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.7736G>C at the cDNA level, p.Arg2579Thr (R2579T) at the protein level, and results in the change of an Arginine to a Threonine (AGA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg2579Thr 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 Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Arg2579Thr occurs at a position that is not conserved 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 Arg2579Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000691617 SCV000819403 uncertain significance Ataxia-telangiectasia syndrome 2018-06-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 2579 of the ATM protein (p.Arg2579Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. 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: 246325). 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 threonine 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 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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