ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8918G>T (p.Arg2973Met) (rs730881331)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159667 SCV000209667 uncertain significance not provided 2014-08-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.8918G>T at the cDNA level, p.Arg2973Met (R2973M) at the protein level, and results in the change of an Arginine to a Methionine (AGG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg2973Met 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 Arginine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg2973Met occurs at a position that is highly conserved through mammals and is located in the region of interaction with p53 (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 Arg2973Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000560399 SCV000622864 uncertain significance Ataxia-telangiectasia syndrome 2017-05-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 2973 of the ATM protein (p.Arg2973Met). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and methionine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181904). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on 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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