ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7108A>G (p.Asn2370Asp) (rs767494363)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588629 SCV000293868 uncertain significance not provided 2016-01-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.7108A>G at the cDNA level, p.Asn2370Asp (N2370D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asn2370Asp 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 Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asn2370Asp occurs at a position that is not conserved and is located within the FAT domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Asn2370Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588629 SCV000694345 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The ATM c.7108A>G (p.Asn2370Asp) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/120934, which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasia. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000689779 SCV000817445 uncertain significance Ataxia-telangiectasia syndrome 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 2370 of the ATM protein (p.Asn2370Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs767494363, ExAC 0.002%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 246353). 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 tolerated, 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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