ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4561G>C (p.Val1521Leu) (rs141329176)

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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 RCV000219002 SCV000273233 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000657107 SCV000293794 uncertain significance not provided 2017-08-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.4561G>C at the cDNA level, p.Val1521Leu (V1521L) at the protein level, and results in the change of a Valine to a Leucine (GTT>CTT). This variant was observed in a normal tissue sample from an individual with clear cell renal cancer (Lu 2015). ATM Val1521Leu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. ATM Val1521Leu occurs at a position that is conserved across species and is not located in a known functional domain. 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 Val1521Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000467522 SCV000546703 uncertain significance Ataxia-telangiectasia syndrome 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1521 of the ATM protein (p.Val1521Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs141329176, 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: 229874). 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.
Genetic Services Laboratory, University of Chicago RCV000235643 SCV000593512 uncertain significance not specified 2017-05-05 criteria provided, single submitter clinical testing

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