ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1727T>C (p.Ile576Thr) (rs730881342)

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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 RCV000159685 SCV000216297 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Color RCV000159685 SCV000913551 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
GeneDx RCV000590025 SCV000209691 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.1727T>C at the cDNA level, p.Ile576Thr (I576T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant was observed by Decker et al. (2017) in 1/13,087 patients with breast cancer and 0/5,488 controls; however, it was also observed by Skowronska et al. (2011) in 1/281 healthy controls but not in 318 patients with chronic lymphocytic leukemia. ATM Ile576Thr was observed at an allele frequency of 0.035% (9/25768) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant 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 Ile576Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590025 SCV000694194 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing Variant summary: The ATM c.1727T>C (p.Ile576Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 16/121784 control chromosomes at a frequency of 0.0001314, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. 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. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000196810 SCV000254063 uncertain significance Ataxia-telangiectasia syndrome 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 576 of the ATM protein (p.Ile576Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs730881342, ExAC 0.02%). This variant has been identified in unaffected individuals as well as in individuals affected with breast cancer (PMID: 21933854, 28779002, Invitae). The individual affected with breast cancer sequenced at Invitae also carried a pathogenic allele in ATM, which suggests that this c.1727T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 181920). 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: "Benign"; Align-GVGD: "Class C65"). 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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