ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7135C>G (p.Leu2379Val) (rs778888033)

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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 RCV000166076 SCV000216839 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166076 SCV000682389 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
GeneDx RCV000236581 SCV000293240 uncertain significance not provided 2018-12-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.7135C>G at the cDNA level, p.Leu2379Val (L2379V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Leu2379Val was observed at an allele frequency of 0.04% (12/33,578) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict that this variant may create a cryptic splice donor site upstream of the natural splice donor site for intron 49. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether ATM Leu2379Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000463701 SCV000546840 uncertain significance Ataxia-telangiectasia syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 2379 of the ATM protein (p.Leu2379Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs778888033, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186475). 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. 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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