ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3055C>G (p.Leu1019Val) (rs863224560)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565743 SCV000667806 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000565743 SCV000687440 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000484897 SCV000564624 uncertain significance not provided 2016-07-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.3055C>G at the cDNA level, p.Leu1019Val (L1019V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in bladder carcinoma (Plimack 2015). ATM Leu1019Val 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 Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1019Val occurs at a position that is conserved across species and is located in the beta-adaptin interaction domain (Tavtigian 2009). 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 Leu1019Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200782 SCV000254079 uncertain significance Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1019 of the ATM protein (p.Leu1019Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. 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: 216199). 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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