ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3331C>G (p.Leu1111Val) (rs587779832)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587896 SCV000149083 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.3331C>G at the cDNA level, p.Leu1111Val (L1111V) 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 pathogenic or benign. ATM Leu1111Val 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 Leu1111Val occurs at a position where amino acids with properties similar to Leucine are tolerated 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 Leu1111Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206179 SCV000260300 uncertain significance Ataxia-telangiectasia syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1111 of the ATM protein (p.Leu1111Val). The leucine residue is moderately 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: 127369). 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.
Ambry Genetics RCV000568599 SCV000665611 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000568599 SCV000682119 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587896 SCV000694256 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The ATM c.3331C>G (p.Leu1111Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this substitution. This variant is absent in 115192 control chromosomes. 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. Multiple clinical diagnostic laboratories/reputable databases classified this variant as Uncertain. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
GeneKor MSA RCV000568599 SCV000821847 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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