ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4606A>G (p.Lys1536Glu) (rs587779841)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212019 SCV000149107 uncertain significance not specified 2016-08-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.4606A>G at the cDNA level, p.Lys1536Glu (K1536E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys1536Glu 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 Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Lys1536Glu occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Lys1536Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115198 SCV000183937 likely benign Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Invitae RCV000465699 SCV000546803 uncertain significance Ataxia-telangiectasia syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1536 of the ATM protein (p.Lys1536Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs587779841, ExAC 0.2%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127393). 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 glutamic acid 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.
PreventionGenetics,PreventionGenetics RCV000679122 SCV000805568 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
Color RCV000115198 SCV000910892 likely benign Hereditary cancer-predisposing syndrome 2015-10-27 criteria provided, single submitter clinical testing

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