ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3530G>C (p.Cys1177Ser) (rs587782470)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131572 SCV000186578 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing
Invitae RCV000198090 SCV000254086 uncertain significance Ataxia-telangiectasia syndrome 2017-06-10 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 1177 of the ATM protein (p.Cys1177Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142446). 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 C0"). In summary, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000485057 SCV000572908 uncertain significance not provided 2017-01-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.3530G>C at the cDNA level, p.Cys1177Ser (C1177S) at the protein level, and results in the change of a Cysteine to a Serine (TGT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Cys1177Ser 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 Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Cys1177Ser occurs at a position that is conserved in mammals and is located in region of interaction with beta-adaptin (Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Cys1177Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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