ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2158C>T (p.Arg720Cys) (rs565622131)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462183 SCV000546688 uncertain significance Ataxia-telangiectasia syndrome 2018-03-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 720 of the ATM protein (p.Arg720Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs565622131, ExAC 0.02%). This variant has been reported in an individual with breast cancer (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 407475). 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.
GeneDx RCV000481591 SCV000566507 uncertain significance not provided 2017-03-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.2158C>T at the cDNA level, p.Arg720Cys (R720C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in 1/2531 breast cancer cases and in none of 2245 controls (Tavtigian 2009). ATM Arg720Cys was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, 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 Arg720Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Arg720Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000566565 SCV000660455 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000566565 SCV000906529 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing

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