ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2005T>C (p.Cys669Arg)

gnomAD frequency: 0.00003  dbSNP: rs587782141
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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 RCV000130699 SCV000185586 likely benign Hereditary cancer-predisposing syndrome 2024-03-21 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV000485416 SCV000567215 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.2005T>C at the cDNA level, p.Cys669Arg (C669R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Cys669Arg occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Cys669Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000549496 SCV000622301 uncertain significance Ataxia-telangiectasia syndrome 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 669 of the ATM protein (p.Cys669Arg). This variant is present in population databases (rs587782141, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 141958). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV000130699 SCV001353171 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-22 criteria provided, single submitter clinical testing This missense variant replaces cysteine with arginine at codon 669 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV004764769 SCV005374675 uncertain significance Hereditary breast ovarian cancer syndrome 2024-06-10 criteria provided, single submitter curation According to the ClinGen ACMG ATM v1.1.0 criteria we chose these criteria: PM2 (supporting pathogenic): not in gnomAD, BP4 (supporting benign): Revel=0.058
Natera, Inc. RCV000549496 SCV002084016 uncertain significance Ataxia-telangiectasia syndrome 2020-12-10 no assertion criteria provided clinical testing

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