ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.616A>C (p.Asn206His) (rs587781829)

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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 RCV000130115 SCV000184945 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000463431 SCV000546814 uncertain significance Ataxia-telangiectasia syndrome 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 206 of the ATM protein (p.Asn206His). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs587781829, ExAC 0.002%). This variant has been reported in an individual with glioblastoma multiforme (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 141543). 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. 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.
GeneDx RCV000480488 SCV000569449 uncertain significance not provided 2016-09-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.616A>C at the cDNA level, p.Asn206His (N206H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant was identified in both the tumor and normal surrounding tissue of an individual with glioblastoma as well as the tumor of an individual with lymphoma (Lu 2015, Parry 2015). ATM Asn206His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asn206His occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Asn206His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000130115 SCV000682310 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing

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