ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6411C>G (p.Asp2137Glu) (rs780299607)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221609 SCV000278080 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000590406 SCV000564651 uncertain significance not provided 2015-02-24 criteria provided, single submitter clinical testing This variant is denoted ATM c.6411C>G at the cDNA level, p.Asp2137Glu (D2137E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asp2137Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. ATM Asp2137Glu occurs at a position that is highly conserved across vertebrates and is located within the FAT domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Asp2137Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000554925 SCV000622666 uncertain significance Ataxia-telangiectasia syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 2137 of the ATM protein (p.Asp2137Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs780299607, 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: 233658). 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.
Color RCV000221609 SCV000682333 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590406 SCV000694323 uncertain significance not provided 2017-03-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.6411C>G (p.Asp2137Glu) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant was found in 1/121172 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). One clinical diagnostic laboratory has classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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