ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8486C>T (p.Pro2829Leu) (rs938431501)

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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 RCV000566971 SCV000665190 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000480686 SCV000566097 uncertain significance not provided 2015-03-31 criteria provided, single submitter clinical testing This variant is denoted ATM c.8486C>T at the cDNA level, p.Pro2829Leu (P2829L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). This variant was observed in the reportedly homozygous state in a case of Ataxia-Telangiectasia (Sasaki 1998). ATM Pro2829Leu 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 Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Pro2829Leu occurs at a position that is conserved across species and is located in the PI3K/PI4K domain (UniProt). Published computational methods by Doss et al. (2012) and in house in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Pro2829Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000792087 SCV000931360 uncertain significance Ataxia-telangiectasia syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2829 of the ATM protein (p.Pro2829Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in an individual affected with ataxia telangiectasia (AT) (PMID: 9711876). ClinVar contains an entry for this variant (Variation ID: 418777). 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 disruptive, 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.

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