ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6392C>A (p.Ala2131Asp) (rs1060501594)

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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 RCV000570727 SCV000668119 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000480424 SCV000569635 uncertain significance not provided 2016-03-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.6392C>A at the cDNA level, p.Ala2131Asp (A2131D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala2131Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ala2131Asp occurs at a position that is conserved in mammals and is located in the within FAT domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Ala2131Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000468871 SCV000546829 uncertain significance Ataxia-telangiectasia syndrome 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 2131 of the ATM protein (p.Ala2131Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. 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: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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