ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3964C>A (p.Leu1322Ile) (rs144535256)

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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 RCV000132364 SCV000187454 likely benign Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s)
Color RCV000132364 SCV000906587 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing
Counsyl RCV000204555 SCV000795641 uncertain significance Ataxia-telangiectasia syndrome 2017-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000237005 SCV000293003 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.3964C>A at the cDNA level, p.Leu1322Ile (L1322I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTT>ATT). In vitro assays by Barone et al. (2009) found ATM Leu1322Ile to demonstrate protein levels and kinase activity equivalent to wild-type. Leu1322Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1322Ile 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 Leu1322Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000204555 SCV000259593 uncertain significance Ataxia-telangiectasia syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 1322 of the ATM protein (p.Leu1322Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs144535256, ExAC 0.005%). This variant has been reported in an individual affected with endometrial carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 142896). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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