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

Total submissions: 3

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.