ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.94C>T (p.Arg32Cys) (rs148061139)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132385 SCV000187476 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000233534 SCV000283106 uncertain significance Ataxia-telangiectasia syndrome 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 32 of the ATM protein (p.Arg32Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs148061139, ExAC 0.07%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142913). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; 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.
GeneDx RCV000236602 SCV000292845 uncertain significance not provided 2016-08-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.94C>T at the cDNA level, p.Arg32Cys (R32C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been identified in at least one individual with an unspecified type of cancer (Petereit 2013). ATM Arg32Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg32Cys occurs at a position that is not conserved across species and is not located in a known functional domain (Tavtigian 2009). 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 Arg32Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Mendelics RCV000233534 SCV000838464 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000132385 SCV000910910 likely benign Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing

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