ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8546G>A (p.Arg2849Gln) (rs587782202)

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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 RCV000130863 SCV000185762 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
GeneDx RCV000482134 SCV000566919 uncertain significance not provided 2017-12-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.8546G>A at the cDNA level, p.Arg2849Gln (R2849Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been identified in at least one breast cancer patient (Decker 2017). ATM Arg2849Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Arg2849Gln is located in the kinase domain (Stracker 2013). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available information, it is unclear whether ATM Arg2849Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000627888 SCV000748772 uncertain significance Ataxia-telangiectasia syndrome 2017-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2849 of the ATM protein (p.Arg2849Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587782202, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142055). 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 disruptive, 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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