ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4868T>C (p.Leu1623Pro) (rs786203017)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166136 SCV000216908 uncertain significance Hereditary cancer-predisposing syndrome 2014-11-06 criteria provided, single submitter clinical testing
Invitae RCV000200850 SCV000254116 uncertain significance Ataxia-telangiectasia syndrome 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1623 of the ATM protein (p.Leu1623Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. 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: 186527). 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, 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.
GeneDx RCV000485111 SCV000567753 uncertain significance not provided 2015-08-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.4868T>C at the cDNA level, p.Leu1623Pro (L1623P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1623Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Leu1623Pro occurs at a position that is not conserved and is not located in a known functional domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Leu1623Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.

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