ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6679C>T (p.Arg2227Cys) (rs564652222)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000159749 SCV000218096 pathogenic Hereditary cancer-predisposing syndrome 2019-03-17 criteria provided, single submitter clinical testing 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
Invitae RCV000196419 SCV000253742 pathogenic Ataxia-telangiectasia syndrome 2020-01-09 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.
Color RCV000159749 SCV000687719 pathogenic Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing
GeneKor MSA RCV000159749 SCV000821702 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This is a single base substitution replacing the amino acid Arginine with Cysteine in the position 2227 of the ATM protein. This particular Arginine is highily conserved and located in a known functional domain, while the physiochemical difference between Arginine and Cysteine is high (Grantham Score 180). This finding is not present in population databases. The mutation database ClinVar contains an entry for this variant (Variation ID: 181981). Algorithms developed to estimate the effect of point mutations on the function and structure of the protein estimate that this change may affect the function or structure of the protein, which is confirmed by recent functional studies of the mutant protein where they showed decreased expression of ATM and reduced ATM kinase activity (PMID: 23640770, PMID: 18634022 ).
Mendelics RCV000196419 SCV000838579 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 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
Integrated Genetics/Laboratory Corporation of America RCV001255479 SCV001431897 pathogenic breast cancer 2020-08-11 criteria provided, single submitter clinical testing Variant summary: ATM c.6679C>T (p.Arg2227Cys) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251146 control chromosomes (gnomAD). c.6679C>T has been reported in the literature in multiple individuals in compound heterozygous state affected with ataxia-telangiectasia and Hodgkin disease (Gutierrez-Enriquez_2004, Mitui_2009, Meissner_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant effect results in reducing ATM protein level, ATM kinase activity and shown as severe in radiation sensitivity (Mitui_2009, Meissner_2013). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000196419 SCV000328269 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only

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