ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7468C>T (p.Leu2490Phe) (rs753262623)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219162 SCV000273256 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000219162 SCV000904731 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-28 criteria provided, single submitter clinical testing
GeneDx RCV000587941 SCV000293273 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.7468C>T at the cDNA level, p.Leu2490Phe (L2490F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. ATM Leu2490Phe VARIANT was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. ATM Leu2490Phe occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Leu2490Phe is pathogenic or benign.
Integrated Genetics/Laboratory Corporation of America RCV000587941 SCV000694353 uncertain significance not provided 2016-09-26 criteria provided, single submitter clinical testing Variant summary: The ATM c.7468C>T (p.Leu2490Phe) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/121360 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been reported in the literature, without strong evidence for causality. In addition, multiple reputable clinical labs/databases have classified this variant as a VUS. Taken together, this variant is classified as VUS.
Invitae RCV000229441 SCV000283056 uncertain significance Ataxia-telangiectasia syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 2490 of the ATM protein (p.Leu2490Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs753262623, ExAC 0.006%). This variant has been reported in an individual affected with lung adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 229889). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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