ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8762C>A (p.Thr2921Lys) (rs730881329)

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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 RCV000159665 SCV000217104 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-17 criteria provided, single submitter clinical testing
Color RCV000159665 SCV000903722 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV000212090 SCV000209664 uncertain significance not provided 2016-11-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.8762C>A at the cDNA level, p.Thr2921Lys (T2921K) at the protein level, and results in the change of a Threonine to a Lysine (ACG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2921Lys 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 Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Thr2921Lys occurs at a position that is conserved across species and is located in the kinase domain (Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Thr2921Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000538842 SCV000622848 uncertain significance Ataxia-telangiectasia syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 2921 of the ATM protein (p.Thr2921Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181902). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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