ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2386A>C (p.Asn796His) (rs201793499)

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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 RCV000130389 SCV000185247 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000479754 SCV000564617 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.2386A>C at the cDNA level, p.Asn796His (N796H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asn796His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asn796His occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Asn796His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000627981 SCV000748868 uncertain significance Ataxia-telangiectasia syndrome 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 796 of the ATM protein (p.Asn796His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs201793499, ExAC 0.002%). This variant has been reported in an individual affected with chronic lymphocytic leukemia (CLL) (PMID: 26837699). ClinVar contains an entry for this variant (Variation ID: 141757). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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