ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7354C>G (p.Leu2452Val) (rs587779863)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212064 SCV000149157 uncertain significance not provided 2016-09-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.7354C>G at the cDNA level, p.Leu2452Val (L2452V) at the protein level, and results in the change of a Leucine to a Valine (CTG>GTG). This variant has not, to our knowledge, been published in the literature as either a pathogenic or benign germline variant. However, it has been reported as a somatic variant in at least one chronic lymphocytic leukemia (CLL) sample (Sutton 2015). ATM Leu2452Val 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 Leu2452Val occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in the FAT domain (Tavtigian 2009, Stracker 2013). 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 Leu2452Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115248 SCV000214337 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-04 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,in silico models in agreement (benign)
Invitae RCV000463953 SCV000546791 uncertain significance Ataxia-telangiectasia syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 2452 of the ATM protein (p.Leu2452Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs587779863, ExAC 0.003%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127442). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000115248 SCV000682407 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing

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