ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1966A>G (p.Thr656Ala) (rs1064793032)

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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 RCV000571860 SCV000665271 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000571860 SCV000682017 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing
GeneDx RCV000479657 SCV000564614 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.1966A>G at the cDNA level, p.Thr656Ala (T656A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr656Ala was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr656Ala occurs at a position that is conserved across species 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 information, it is unclear whether ATM Thr656Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000692298 SCV000820112 uncertain significance Ataxia-telangiectasia syndrome 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 656 of the ATM protein (p.Thr656Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. 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: 418025). 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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