ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3341A>G (p.Lys1114Arg) (rs777705500)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221075 SCV000275432 likely benign Hereditary cancer-predisposing syndrome 2017-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Other strong data supporting benign classification,In silico models in agreement (benign)
GeneDx RCV000481285 SCV000566269 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.3341A>G at the cDNA level, p.Lys1114Arg (K1114R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been observed as a somatic variant in a breast tumor (Knappskog 2012). ATM Lys1114Arg was not observed in large population cohorts (Lek 2016). This variant is located within the region of interaction with beta-adaptin (Tavtigian 2009). 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 Lys1114Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524647 SCV000622411 uncertain significance Ataxia-telangiectasia syndrome 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1114 of the ATM protein (p.Lys1114Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with breast cancer (PMID: 22420423) . ClinVar contains an entry for this variant (Variation ID: 231546). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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