ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7375C>G (p.Arg2459Gly) (rs730881383)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159750 SCV000217280 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Athena Diagnostics Inc RCV000212066 SCV000840959 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing
Color RCV000159750 SCV000682409 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000212066 SCV000209766 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.7375C>G at the cDNA level, p.Arg2459Gly (R2459G) at the protein level, and results in the change of an Arginine to a Glycine (CGT>GGT). This variant has been observed in individuals with ovarian, colon, or lung cancer, and also in a proband meeting clinical criteria for Neurofibromatosis Type 1 (Kanchi 2014, Lu 2015, Castellanos 2017, Parry 2017, Yurgelun 2017). ATM Arg2459Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Arg2459Gly is located in the FAT domain (Stracker 2013). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, splicing models predict the creation of a novel cryptic splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether ATM Arg2459Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228814 SCV000283050 uncertain significance Ataxia-telangiectasia syndrome 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 2459 of the ATM protein (p.Arg2459Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs730881383, ExAC 0.03%). This variant has been reported in individuals affected with ovarian cancer and colorectal cancer (PMID: 24448499, 26689913, 28135145). ClinVar contains an entry for this variant (Variation ID: 181982). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
Mendelics RCV000228814 SCV000838592 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Research and Development,Genoox RCV000212066 SCV000916302 uncertain significance not provided no assertion criteria provided clinical testing

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