ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8494C>T (p.Arg2832Cys) (rs587779872)

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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 RCV000115265 SCV000186811 pathogenic Hereditary cancer-predisposing syndrome 2017-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
Color RCV000115265 SCV000682491 pathogenic Hereditary cancer-predisposing syndrome 2017-03-27 criteria provided, single submitter clinical testing
Counsyl RCV000169354 SCV000220724 likely pathogenic Ataxia-telangiectasia syndrome 2014-09-23 criteria provided, single submitter literature only
GeneDx RCV000212084 SCV000149174 pathogenic not provided 2018-10-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.8494C>T at the cDNA level, p.Arg2832Cys (R2832C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). ATM Arg2832Cys has been reported in association with a mild presentation of recessively-inherited ataxia telangiectasia (Telatar 1998, Buzin 2003, Mitui 2009), and in individuals with breast cancer, colorectal cancer, and family history of breast and/or ovarian cancer (Schroeder 2015, Hansen 2017, Pritzlaff 2017, Renault 2018). Some functional studies have demonstrated reduced amount of ATM protein, no detectable kinase activity, and intermediate radiosensitivity associated with Arg2832Cys (Becker-Catania 2000, Mitui 2009), while others showed reduced, but not absent, ATM kinase activity and a low level of ATM protein (Sun 2002, Butch 2004, Chun 2004, Barone 2009, Reiman 2011). ATM Arg2832Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Arg2832Cys is located in the kinase domain (Stracker 2013). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
GeneReviews RCV000169354 SCV000328272 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Invitae RCV000169354 SCV000260807 pathogenic Ataxia-telangiectasia syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2832 of the ATM protein (p.Arg2832Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587779872, ExAC 0.001%). This variant has been reported in individuals affected with ataxia-telangiectasia (A-T), in individuals with breast cancer in A-T families (PMID: 9443866, 10817650, 10873394, 18634022, 12552559), and in individuals affected with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 127459). This variant affects a moderately conserved amino acid in the semi-conserved region of the PI3-kinase domain in the ATM protein (PMID: 10873394). Functional studies of this sequence change in transfected human cells show trace levels of ATM protein expression and intermediate colony survival rates (PMID: 10873394, 19431188). Furthermore, functional studies in cell lines from affected individuals that carry this sequence change along with a nonsense or other missense variant also show decreased colony survival rate (PMID: 18634022). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000169354 SCV000809109 pathogenic Ataxia-telangiectasia syndrome 2018-07-10 criteria provided, single submitter clinical testing
Mendelics RCV000169354 SCV000838615 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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