ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.826A>G (p.Lys276Glu) (rs587782902)

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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 RCV000132545 SCV000187643 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-28 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 or conflicting evidence
GeneDx RCV000520768 SCV000618295 uncertain significance not provided 2017-02-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.826A>G at the cDNA level, p.Lys276Glu (K276E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys276Glu was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Lys276Glu occurs at a position that is conserved across species and is not located in a known functional domain. Based on currently available evidence, it is unclear whether ATM Lys276Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000699534 SCV000828249 uncertain significance Ataxia-telangiectasia syndrome 2018-06-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 276 of the ATM protein (p.Lys276Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 143025). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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