ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7997C>A (p.Thr2666Asn) (rs730881384)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159752 SCV000209768 likely pathogenic not provided 2017-07-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.7997C>A at the cDNA level, p.Thr2666Asn (T2666N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). This variant was observed in an individual with an abnormality of the nervous system (Retterer 2016); specifically it was observed at our laboratory in trans with an ATM nonsense variant in several patients from a family, all of which had a clinical presentation consistent with Ataxia Telangiectasia. ATM Thr2666Asn was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Asparagine share similar properties, this is considered a conservative amino acid substitution. ATM Thr2666Asn occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider ATM Thr2666Asn to be a likely pathogenic variant.
Invitae RCV000628059 SCV000748948 uncertain significance Ataxia-telangiectasia syndrome 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 2666 of the ATM protein (p.Thr2666Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with a disorder of the central nervous system (PMID: 26633542). ClinVar contains an entry for this variant (Variation ID: 181984). 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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