ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7357C>T (p.Arg2453Cys) (rs755418571)

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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 RCV000221466 SCV000273895 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000478875 SCV000565899 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.7357C>T at the cDNA level, p.Arg2453Cys (R2453C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). ATM Arg2453Cys was identified in at least one individual in the Breast Cancer Family Registry (Goldgar 2011). ATM Arg2453Cys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg2453Cys occurs at a position that is not conserved and is located in the FAT 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 Arg2453Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000534667 SCV000622739 uncertain significance Ataxia-telangiectasia syndrome 2018-11-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2453 of the ATM protein (p.Arg2453Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs755418571, ExAC 0.002%) but has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 230366). 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: "Possibly 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.
Color RCV000221466 SCV000682408 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing

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