ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8906A>G (p.Tyr2969Cys) (rs376524155)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214134 SCV000273392 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000521477 SCV000617086 uncertain significance not provided 2017-03-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.8906A>G at the cDNA level, p.Tyr2969Cys (Y2969C) 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 Tyr2969Cys was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr2969Cys occurs at a position that is conserved through mammals and is located in the FATC domain (Stracker 2013). 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 Tyr2969Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000627975 SCV000748862 uncertain significance Ataxia-telangiectasia syndrome 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2969 of the ATM protein (p.Tyr2969Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs376524155, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 229994). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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