ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1631T>C (p.Leu544Ser) (rs375754332)

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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 RCV000164434 SCV000215073 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000588135 SCV000566873 uncertain significance not provided 2018-11-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.1631T>C at the cDNA level, p.Leu544Ser (L544S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). This variant has been observed in at least one individual undergoing multigene hereditary cancer panel testing (Mu 2016). ATM Leu544Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Leu544Ser is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Leu544Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000531488 SCV000622274 uncertain significance Ataxia-telangiectasia syndrome 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 544 of the ATM protein (p.Leu544Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs375754332, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 185076). 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.
Integrated Genetics/Laboratory Corporation of America RCV000588135 SCV000694190 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The c. 1631T>C (p.Le544Ser) in ATM gene is a missense change that involves a mildly conserved nucleotide and 2/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain. The variant is present in the control population dataset of ExAC at frequency of 0.0000008 (1/123134 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0001, suggesting that it is not a common polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports. The variant of interest has been reported as VUS by reputable database/clinical laboratory. Taking together, the variant was classified as VUS until more information becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000588135 SCV000703944 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing

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