ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3078G>T (p.Trp1026Cys) (rs876660869)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219464 SCV000278646 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Invitae RCV000704906 SCV000833879 uncertain significance Ataxia-telangiectasia syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 1026 of the ATM protein (p.Trp1026Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with ataxia-telangectasia  (PMID: 28126470, 23726790). A second pathogenic variant was identified in each individual which is consistent with autosomal recessive disease inheritance. ClinVar contains an entry for this variant (Variation ID: 234132). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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