ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8549T>C (p.Leu2850Ser) (rs876658716)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479563 SCV000571335 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.8549T>C at the cDNA level, p.Leu2850Ser (L2850S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu2850Ser 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 Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Leu2850Ser occurs at a position that is conserved and is located in the PI3/PI4 kinase domain (Tavtigian 2009, 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 Leu2850Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000580976 SCV000682496 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-24 criteria provided, single submitter clinical testing
GeneKor MSA RCV000580976 SCV000821879 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000819032 SCV000959673 uncertain significance Ataxia-telangiectasia syndrome 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 2850 of the ATM protein (p.Leu2850Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. 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: 421983). 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 disruptive, 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.

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