ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5750G>C (p.Arg1917Thr) (rs377289524)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129190 SCV000183928 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000129190 SCV000687638 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing
GeneDx RCV000486854 SCV000567742 uncertain significance not provided 2018-04-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.5750G>C at the cDNA level, p.Arg1917Thr (R1917T) at the protein level, and results in the change of an Arginine to a Threonine (AGA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg1917Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Arg1917Thr is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg1917Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000471458 SCV000547047 uncertain significance Ataxia-telangiectasia syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 1917 of the ATM protein (p.Arg1917Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is present in population databases (rs377289524, ExAC 0.002%). This variant has not been reported in the germline of individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 140925). 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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