ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8624A>G (p.Asn2875Ser) (rs587782451)

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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 RCV000131523 SCV000186517 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
GeneDx RCV000520477 SCV000617377 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing This apparently mosaic variant is denoted ATM c.8624A>G at the cDNA level, p.Asn2875Ser (N2875S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was observed along with a nonsense ATM variant in at least one patient with ataxia telangiectasia (Anheim 2010). ATM Asn2875Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. ATM Asn2875Ser occurs at a position that is conserved across species and is located within the catalytic region of the kinase domain (Lavin 2004, Stracker 2013) In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Asn2875Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000458955 SCV000547140 uncertain significance Ataxia-telangiectasia syndrome 2016-05-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2875 of the ATM protein (p.Asn2875Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs587782451, ExAC <0.01%). This variant has been reported in an individual affected with ataxia-telangiectasia (A-T) with a second ATM deleterious variant (PMID: 19440741). ClinVar contains an entry for this variant (Variation ID: 142418). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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