ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4201T>A (p.Leu1401Ile) (rs587779838)

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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 RCV000568754 SCV000660496 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000568754 SCV000906687 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000115188 SCV000149097 uncertain significance not provided 2017-02-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.4201T>A at the cDNA level, p.Leu1401Ile (L1401I) at the protein level, and results in the change of a Leucine to an Isoleucine (TTA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1401Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1401Ile occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Leu1401Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000468550 SCV000547021 uncertain significance Ataxia-telangiectasia syndrome 2017-09-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 1401 of the ATM protein (p.Leu1401Ile). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127383). 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, this variant has uncertain impact on ATM function. 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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