ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.9022C>T (p.Arg3008Cys) (rs587782292)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131173 SCV000186119 pathogenic Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing Well-characterized mutation at same position;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function in appropriate functional assay(s)
GeneDx RCV000212096 SCV000209774 pathogenic not provided 2018-01-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.9022C>T at the cDNA level, p.Arg3008Cys (R3008C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been observed in both the homozygous and compound heterozygous state in multiple individuals with Ataxia-telangiectasia (Hacia 1998, Li 2000, Angele 2003, Reiman 2011, Carney 2012) and has been shown in functional studies to abolish ATM kinase activity (Angele 2003, Austen 2008, Barone 2009). This variant has also been observed in the heterozygous state in at least one individual with familial breast cancer (Aloraifi 2015). ATM Arg3008Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FATC domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the current evidence, we consider this variant to be pathogenic.
Counsyl RCV000169274 SCV000220577 likely pathogenic Ataxia-telangiectasia syndrome 2014-08-06 criteria provided, single submitter literature only
Invitae RCV000169274 SCV000259422 pathogenic Ataxia-telangiectasia syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 3008 of the ATM protein (p.Arg3008Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587782292, ExAC 0.01%). This variant has been reported in individuals affected with ataxia-telangiectasia (A-T), as homozygous as well as compound heterozygous with a second pathogenic ATM variant in trans (PMID: 9872980, 10817650, 12552566). This variant has also been reported in an individual with breast cancer (PMID: 26094658). ClinVar contains an entry for this variant (Variation ID: 142187). Experimental studies have shown that this missense change results in inactivation of ATM kinase activity, increased radio-sensitivity, and cell cycle defects in vitro (PMID: 12552566, 15101044, 18573109). For these reasons, this variant has been classified as Pathogenic.
Color RCV000131173 SCV000687871 pathogenic Hereditary cancer-predisposing syndrome 2015-02-17 criteria provided, single submitter clinical testing
Mendelics RCV000169274 SCV000838622 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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