ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6145T>G (p.Tyr2049Asp) (rs786203767)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167214 SCV000218051 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Insufficient evidence
Counsyl RCV000628069 SCV000797277 uncertain significance Ataxia-telangiectasia syndrome 2018-01-19 criteria provided, single submitter clinical testing
GeneDx RCV000523725 SCV000616646 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.6145T>G at the cDNA level, p.Tyr2049Asp (Y2049D) at the protein level,and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). This variant was observed in the compoundheterozygous state with another ATM variant in a pediatric patient with ataxia-telangiectasia (Podralska 2014). ATMTyr2049Asp was not observed in large population cohorts (Lek 2016). Since Tyrosine and Aspartic Acid differ inpolarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATMTyr2049Asp occurs at a position that is conserved across species and is located within the FAT domain (Stracker2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based oncurrently available information, it is unclear whether ATM Tyr2049Asp is pathogenic or benign. We consider it to be avariant of uncertain significance
Invitae RCV000628069 SCV000748958 uncertain significance Ataxia-telangiectasia syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 2049 of the ATM protein (p.Tyr2049Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ataxia telangiectasia (PMID: 25614872). ClinVar contains an entry for this variant (Variation ID: 187481). 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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