ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1792A>G (p.Ile598Val) (rs730881343)

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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 RCV000159686 SCV000217865 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000159686 SCV000681999 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing
GeneDx RCV000211969 SCV000209692 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.1792A>G at the cDNA level, p.Ile598Val (I598V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has been observed in at least one individual with breast cancer as well as at least one control individual (Knappskog 2012, Pritchard 2018). ATM Ile598Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether ATM Ile598Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780876 SCV000918501 uncertain significance not specified 2017-10-12 criteria provided, single submitter clinical testing Variant summary: The c.1792A>G (p.Ile598Val) in ATM gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is located outside of any known domain or repeat, and no functional studied suggesting the impact of this change on protein function were published at the time of evaluation. The c.1792A>G is present in the control population dataset of gnomAD at a low frequency of 0.000004 (1/ 245020 chrs tested), which frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.001. The variant has been reported in at least one brC patient without strong evidence for causality. Lastly, the variant of interest is cited as VUS by reputable databases/clinical laboratories. Taken together, due to the lack of supportive evidence, the variant was classified as VUS, until new information becomes available.
Invitae RCV000462248 SCV000546734 uncertain significance Ataxia-telangiectasia syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 598 of the ATM protein (p.Ile598Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (rs730881343, ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 22420423). ClinVar contains an entry for this variant (Variation ID: 181921). 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. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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