ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4776G>C (p.Glu1592Asp) (rs786202973)

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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 RCV000166063 SCV000216825 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-08 criteria provided, single submitter clinical testing
Invitae RCV000548784 SCV000622531 uncertain significance Ataxia-telangiectasia syndrome 2017-01-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1592 of the ATM protein (p.Glu1592Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant also falls at the last nucleotide of exon 31 of the ATM coding sequence. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186464). 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. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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