ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9023G>A (p.Arg3008His) (rs587781894)

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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 RCV000130230 SCV000185070 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-20 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
Color RCV000130230 SCV000687872 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000254719 SCV000322217 likely pathogenic not provided 2018-08-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.9023G>A at the cDNA level, p.Arg3008His (R3008H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been reported in at least one individual with breast cancer and another with Ataxia-telangiectasia who also harbored an ATM nonsense variant, although phase was not reported (Paglia 2010, Micol 2011). Camacho et al. (2002) reported this variant resulted in reduced ATM protein expression levels while Navrkalova et al. (2013) reported normal protein expression, but deficient p21 activation. ATM Arg3008His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. ATM Arg3008His occurs at a position that is conserved across species and is located in the FATC domain (Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider ATM Arg3008His to be a likely pathogenic variant.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785392 SCV000923963 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000196159 SCV000253673 likely pathogenic Ataxia-telangiectasia syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 3008 of the ATM protein (p.Arg3008His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587781894, ExAC 0.001%). This variant has been reported in an individual with ataxia-telangiectasia (A-T) in combination with a pathogenic (p.Arg1466*) variant (PMID: 21665257). This variant has also been reported in an individual with breast cancer (PMID: 19404735). ClinVar contains an entry for this variant (Variation ID: 141634). This variant has also been reported in tumor samples from individuals with chronic lymphocytic leukemia, mantle cell lymphoma and malignant B-cell lymphoma with either a 11q deletion or with a pathogenic ATM variant (PMID: 17968022, 21933854, 23585524, 12697903, 10397742, 11756177). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg3008Cys) has been determined to be pathogenic (PMID: 9872980, 10817650, 12552566, 15101044, 18573109, 19431188). This suggests that the arginine residue is critical for ATM protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mendelics RCV000196159 SCV000838623 likely pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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