ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6823A>G (p.Ile2275Val) (rs587779857)

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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 RCV000219191 SCV000275025 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000219191 SCV000911406 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000589270 SCV000209634 uncertain significance not provided 2017-03-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.6823A>G at the cDNA level, p.Ile2275Val (I2275V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile2275Val was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Ile2275Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the FAT domain (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 Ile2275Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589270 SCV000694334 uncertain significance not provided 2016-05-20 criteria provided, single submitter clinical testing Variant summary: The ATM c.6823A>G (p.Ile2275Val) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (MutationTaster not counted due to low confidence value). This variant was found in 1/120930 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). One reputable clinical diagnostic laboratory has classified this variant as a VUS. 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 was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000456777 SCV000546845 uncertain significance Ataxia-telangiectasia syndrome 2018-11-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2275 of the ATM protein (p.Ile2275Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs587779857, ExAC 0.002%) but has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181885). 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 valine 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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