ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4658A>C (p.Glu1553Ala) (rs587778075)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166074 SCV000216837 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence
Color RCV000166074 SCV000906622 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Counsyl RCV000200014 SCV000796237 uncertain significance Ataxia-telangiectasia syndrome 2017-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000656761 SCV000292470 uncertain significance not provided 2018-11-24 criteria provided, single submitter clinical testing This variant is denoted ATM c.4658A>C at the cDNA level, p.Glu1553Ala (E1553A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant was observed in at least one individual with breast cancer (Tung 2015), as well as in 1/43 healthy African individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the latter study were younger than 50 years old, thus the unaffected status of this individual may not be significant. ATM Glu1553Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Glu1553Ala 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 Glu1553Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120140 SCV000084280 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000200014 SCV000254113 uncertain significance Ataxia-telangiectasia syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1553 of the ATM protein (p.Glu1553Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs587778075, 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: 133620). 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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