ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.134G>A (p.Arg45Gln) (rs762382111)

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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 RCV000217445 SCV000276184 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-05 criteria provided, single submitter clinical testing
Color RCV000217445 SCV000913527 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-05 criteria provided, single submitter clinical testing
GeneDx RCV000235357 SCV000293679 uncertain significance not provided 2017-03-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.134G>A at the cDNA level, p.Arg45Gln (R45Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg45Gln was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Arg45Gln occurs at a position that is not conserved and is not located in a known functional domain. 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 Arg45Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168047 SCV000218700 uncertain significance Ataxia-telangiectasia syndrome 2018-05-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 45 of the ATM protein (p.Arg45Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs762382111, ExAC 0.009%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 188157). 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 glutamine 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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