ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2005T>C (p.Cys669Arg) (rs587782141)

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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 RCV000130699 SCV000185586 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000485416 SCV000567215 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.2005T>C at the cDNA level, p.Cys669Arg (C669R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Cys669Arg occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Cys669Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000549496 SCV000622301 uncertain significance Ataxia-telangiectasia syndrome 2019-08-23 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 669 of the ATM protein (p.Cys669Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. 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: 141958). 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 tolerated, 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.
Color RCV000130699 SCV001353171 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-04 criteria provided, single submitter clinical testing

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