ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6239A>G (p.Tyr2080Cys) (rs587779855)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115229 SCV000184429 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000115229 SCV000682317 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000212043 SCV000149138 uncertain significance not provided 2015-09-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.6239A>G at the cDNA level, p.Tyr2080Cys (Y2080C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr2080Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr2080Cys occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Tyr2080Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000627951 SCV000748837 uncertain significance Ataxia-telangiectasia syndrome 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2080 of the ATM protein (p.Tyr2080Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine 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: 127424). 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.

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