ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3174G>C (p.Trp1058Cys) (rs1064796080)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481827 SCV000572501 uncertain significance not provided 2016-12-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.3174G>C at the cDNA level, p.Trp1058Cys (W1058C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Trp1058Cys 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 Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Trp1058Cys occurs at a position that is conserved across species and is located in the region of interaction with beta-adaptin (Tavtigian 2009). 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 Trp1058Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000556279 SCV000622393 uncertain significance Ataxia-telangiectasia syndrome 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 1058 of the ATM protein (p.Trp1058Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. 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: 422903). 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 and their clinical significance is uncertain. 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.
Ambry Genetics RCV000574851 SCV000668008 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species

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