ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7522G>A (p.Gly2508Arg) (rs754395517)

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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 RCV000166982 SCV000217803 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166982 SCV000682423 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000235394 SCV000292482 uncertain significance not provided 2017-01-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.7522G>A at the cDNA level, p.Gly2508Arg (G2508R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has been identified in an individual with a personal history of a Lynch syndrome-associated cancer and/or polyps, as well as in normal tissue from an individual with glioblastoma multiforme (Yurgelun 2015, Lu 2015). ATM Gly2508Arg 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 Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Gly2508Arg occurs at a position where amino acids with properties similar to Glycine are tolerated across species, and is located in the FAT domain (Stracker 2013). 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 Gly2508Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000461205 SCV000547137 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2508 of the ATM protein (p.Gly2508Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs754395517, ExAC 0.01%). This variant has been reported in an individual undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 187265). 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 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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