ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5917A>G (p.Arg1973Gly) (rs786202089)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164728 SCV000215400 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000164728 SCV000687652 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000481261 SCV000567617 uncertain significance not provided 2017-08-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.5917A>G at the cDNA level, p.Arg1973Gly (R1973G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg1973Gly was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg1973Gly occurs at a position that is conserved in mammals and is located within the FAT domain (Stracker 2013). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may damage the nearby natural splice donor site and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether ATM Arg1973Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000227713 SCV000283001 uncertain significance Ataxia-telangiectasia syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1973 of the ATM protein (p.Arg1973Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 185328). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, 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 RCV000227713 SCV000838562 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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