ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8663T>C (p.Ile2888Thr) (rs760955058)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236304 SCV000293005 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted ATM c.8663T>C at the cDNA level, p.Ile2888Thr (I2888T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has been observed in at least one individual with chronic lymphocytic leukemia, and in at least one individual with triple negative breast cancer (Skowronska 2012, Couch 2015). ATM Ile2888Thr was not observed in large population cohorts (Lek 2016). This variant is located within the kinase domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ile2888Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000468411 SCV000546786 uncertain significance Ataxia-telangiectasia syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2888 of the ATM protein (p.Ile2888Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with chronic lymphocytic leukemia (CLL) and in an individual affected with triple-negative breast cancer (PMID: 21933854, 25452441). ClinVar contains an entry for this variant (Variation ID: 245842). 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.
Ambry Genetics RCV000563977 SCV000667960 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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