ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5858C>T (p.Thr1953Ile) (rs587781963)

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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 RCV000130342 SCV000185193 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-02 criteria provided, single submitter clinical testing ​The p.T1953I variant (also known as c.5858C>T) is located in coding exon 38 of the ATM gene. This alteration results from a C to T substitution at nucleotide position 5858. The threonine at codon 1953 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in conjunction with another ATM alteration, p.W2109G, in an individual diagnosed with atypical AT who presented with truncal ataxia and telangiectasia since childhood (Mitui, M et al. Hum Mutat. 2009 Jan;30(1):12-21). Functional studies performed by Mitui et al. showed reduced expression and intermediate radiosensitivity, and led the authors to conclude that this alteration is most likely a "kinase-impaired" protein. Based on protein sequence alignment, this amino acid position is completely conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000130342 SCV001350791 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-26 criteria provided, single submitter clinical testing
Invitae RCV001242207 SCV001415278 uncertain significance Ataxia-telangiectasia syndrome 2019-06-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1953 of the ATM protein (p.Thr1953Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ataxia-telangiectasia (PMID: 18634022). ClinVar contains an entry for this variant (Variation ID: 141721). This variant has been reported to affect ATM protein function (PMID: 18634022). 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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