ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6577G>A (p.Val2193Ile) (rs754555043)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215163 SCV000275997 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000215163 SCV000904710 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000235792 SCV000293880 uncertain significance not provided 2018-01-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.6577G>A at the cDNA level, p.Val2193Ile (V2193I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant was observed in a blood sample from a patient with leukemia (McKeown 2017). ATM Val2193Ile was not observed in large population cohorts (Lek 2016). This variant is located in within the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val2193Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000461049 SCV000546748 uncertain significance Ataxia-telangiectasia syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2193 of the ATM protein (p.Val2193Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs754555043, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 231987). 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 isoleucine 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 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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