ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6325T>G (p.Trp2109Gly) (rs1060501654)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463293 SCV000547000 uncertain significance Ataxia-telangiectasia syndrome 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with glycine at codon 2109 of the ATM protein (p.Trp2109Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is not present in population databases (ExAC no frequency). This variant occurs with a second rare variant (p.Thr1953Ile) in ATM in one individual affected with ataxia-telangiectasia, although it is unknown if these two variants are on the same or opposite chromosomes (PMID: 18634022). It was also reported in a family in which 2 individuals were affected with an atypical and late-onset form of ataxia-telangiectasia, and were homozygous for the variant (PMID: 20480175). These observations suggest the c.6325T>G substitution may contribute to the cause of disease. ClinVar contains an entry for this variant (Variation ID: 407649). Experimental studies have shown that this missense change does not alter ATM expression levels, kinase activity, or radiosensitivity in vitro (PMID: 18634022). However, these experiments did not assess other potential functional effects of the variant on ATM function, such as RNA processing. 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.
GeneDx RCV000478293 SCV000566374 uncertain significance not provided 2016-06-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.6325T>G at the cDNA level, p.Trp2109Gly (W2109G) at the protein level, and results in the change of a Tryptophan to a Glycine (TGG>GGG). This variant has been reported in the homozygous and compound heterozygous state in at least three individuals with later onset, atypical Ataxia-telangiectasia (Mitui 2009, Silvestri 2010). Of note, functional assays of this variant have produced conflicting results, demonstrating absent ATM protein by immunoblotting (Silvestri 2010), while additional analyses demonstrated this variant to have no effect on protein level, autophosphorylation ability and radiosensitivity (Mitui 2009). ATM Trp2109Gly 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 Tryptophan and Glycine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Trp2109Gly occurs at a position that is conserved across species and is located in the FAT 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 Trp2109Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562429 SCV000668160 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence,Insufficient evidence

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