ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8558C>G (p.Thr2853Arg) (rs141534716)

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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 RCV000564804 SCV000665596 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000547519 SCV000800280 uncertain significance Ataxia-telangiectasia syndrome 2018-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000115266 SCV000149175 uncertain significance not provided 2014-02-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.8558C>G at the cDNA level, p.Thr2853Arg (T2853R) at the protein level, and results in the change of a Threonine to an Arginine (ACG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2853Arg 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. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is fully conserved throughout evolution and is located within the Phosphatidylinositol 3- and 4-kinase domain (UniProt). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on the currently available information, we consider ATM Thr2853Arg to be a variant of uncertain significance.
Invitae RCV000547519 SCV000622829 uncertain significance Ataxia-telangiectasia syndrome 2018-04-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 2853 of the ATM protein (p.Thr2853Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 127460). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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