ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3613C>T (p.Arg1205Cys) (rs760928285)

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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 RCV000562379 SCV000665272 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000562379 SCV000911420 likely benign Hereditary cancer-predisposing syndrome 2016-06-30 criteria provided, single submitter clinical testing
GeneDx RCV000479830 SCV000572291 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.3613C>T at the cDNA level, p.Arg1205Cys (R1205C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg1205Cys 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 Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg1205Cys occurs at a position that is not conserved and is located in the region of interaction with beta-adaptin (Tavtigian 2009). 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 Arg1205Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000195728 SCV000254088 uncertain significance Ataxia-telangiectasia syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1205 of the ATM protein (p.Arg1205Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs760928285, ExAC 0.006%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 216202). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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