ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.590G>A (p.Gly197Glu) (rs753806542)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482564 SCV000568313 uncertain significance not provided 2016-09-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.590G>A at the cDNA level, p.Gly197Glu (G197E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has been observed in the apparently homozygous state in an individual with atypical Ataxia-Telantiectasia, from whom a cell line was derived and upon examination, exhibited reduced ATM protein and a low level of kinase activity (Carrillo 2009). ATM Gly197Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Gly197Glu occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Gly197Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569534 SCV000667821 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-10 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000569534 SCV000913532 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-04 criteria provided, single submitter clinical testing
Invitae RCV000806962 SCV000946986 uncertain significance Ataxia-telangiectasia syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 197 of the ATM protein (p.Gly197Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs753806542, ExAC 0.03%). This variant has been observed to be homozygous in an individual affected with atypical ataxia-telangiectasia (PMID: 18846412). ClinVar contains an entry for this variant (Variation ID: 420008). Experimental studies have shown that this missense change results in reduced expression of the ATM protein and a low level of the kinase activity (PMID: 18846412). 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.

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