ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4445G>A (p.Cys1482Tyr) (rs201277352)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164631 SCV000215295 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164631 SCV000682208 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Counsyl RCV000461400 SCV000791973 uncertain significance Ataxia-telangiectasia syndrome 2017-06-02 criteria provided, single submitter clinical testing
GeneDx RCV000484293 SCV000566725 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.4445G>A at the cDNA level, p.Cys1482Tyr (C1482Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been observed in individuals with lung adenocarcinoma or breast cancer (Lu 2015, Tung 2015). ATM Cys1482Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Cys1482Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000461400 SCV000546851 uncertain significance Ataxia-telangiectasia syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1482 of the ATM protein (p.Cys1482Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs201277352, ExAC 0.004%). This variant has been reported in an individual affected with lung adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 185247). 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 tolerated, 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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