ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6062G>A (p.Cys2021Tyr) (rs876660062)

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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 RCV000219033 SCV000277166 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-13 criteria provided, single submitter clinical testing
GeneDx RCV000483458 SCV000570592 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.6062G>A at the cDNA level, p.Cys2021Tyr (C2021Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant was observed in an individual with lung cancer (Suzuki 2013). ATM Cys2021Tyr 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 Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Cys2021Tyr occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Cys2021Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000688776 SCV000816400 uncertain significance Ataxia-telangiectasia syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 2021 of the ATM protein (p.Cys2021Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. 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: 232903). 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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