ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6679C>T (p.Arg2227Cys) (rs564652222)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159749 SCV000218096 pathogenic Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,Deficient protein function by in vitro/ex vivo assay
Color RCV000159749 SCV000687719 pathogenic Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762827 SCV000893185 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000212048 SCV000209765 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.6679C>T at the cDNA level, p.Arg2227Cys (R2227C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in the compound heterozygous state in multiple patients with Ataxia-telangiectasia (A-T), as well as in individuals with breast cancer and Hodgkin's lymphoma (Sandoval 1999, Becker-Catania 2000, Buzin 2003, Jiang 2006, Mitui 2009, Verhagen 2012, Zannolli 2012, Meissner 2013, Harbort 2015, Sun 2017). Multiple in vitro functional studies showed decreased levels of ATM protein expression and kinase activity in cell lines with this variant (Becker-Catania 2000, Mitui 2009, Meissner 2013). ATM Arg2227Cys was not observed in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
GeneKor MSA RCV000159749 SCV000821702 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneReviews RCV000196419 SCV000328269 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Invitae RCV000196419 SCV000253742 pathogenic Ataxia-telangiectasia syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2227 of the ATM protein (p.Arg2227Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the compound heterozygous state in several families affected with ataxia-telangiectasia (A-T) (PMID: 12552559, 15843990, 16380133, 19691550, 23264026, 23640770, 18504682, 22213089). In one of these families, this variant was reported to co-segregate in 3 affected siblings (PMID: 23640770). ClinVar contains an entry for this variant (Variation ID: 181981). Experimental studies have shown that this missense change may result in reduced ATM protein expression, as well as reduced ATM kinase activity (PMID: 18634022, 23640770). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000196419 SCV000838579 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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