ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8400G>C (p.Gln2800His) (rs879253901)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561460 SCV000668143 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient evidence
GeneDx RCV000235765 SCV000292735 uncertain significance not provided 2015-10-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.8400G>C at the cDNA level, p.Gln2800His (Q2800H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant 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 Glutamine and Histidine differ is some properties, this is considered a semi-conservative amino acid substitution. ATM Gln2800His occurs at a position that is conserved in mammals and is located in the PI3K/PI4K and Kinase domains (Tavtigian 2009, Stracker 2013, Uniprot). 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 Gln2800His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000628196 SCV000749089 uncertain significance Ataxia-telangiectasia syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 2800 of the ATM protein (p.Gln2800His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 245689). 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 histidine 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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