ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1695A>G (p.Glu565=) (rs780932013)

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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 RCV000563909 SCV000660618 likely benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign
Color RCV000563909 SCV000681992 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
GeneDx RCV000483767 SCV000567907 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.1695A>G at the DNA level. It is silent at the coding level, preserving a Glutamic Acid at codon 565. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM c.1695A>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether ATM c.1695A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779760 SCV000916536 uncertain significance not specified 2017-09-28 criteria provided, single submitter clinical testing Variant summary: The ATM c.1695A>G (p.Glu565Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the variant may impact normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/277036 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000472970 SCV000547136 uncertain significance Ataxia-telangiectasia syndrome 2018-11-01 criteria provided, single submitter clinical testing This sequence change affects codon 565 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. This variant is present in population databases (rs780932013, ExAC 0.001%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 407723). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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