ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8353G>A (p.Asp2785Asn) (rs587782417)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131464 SCV000186449 likely benign Hereditary cancer-predisposing syndrome 2016-12-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000131464 SCV000904752 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Counsyl RCV000198515 SCV000792425 uncertain significance Ataxia-telangiectasia syndrome 2017-06-23 criteria provided, single submitter clinical testing
GeneDx RCV000479519 SCV000565716 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.8353G>A at the cDNA level, p.Asp2785Asn (D2785N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has been reported in one meta-analysis case-control study; it was observed in 1/2245 control subjects but not in 2531 individuals with a history of breast cancer (Tavtigian 2009). ATM Asp2785Asn was not observed at a significant frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asp2785Asn occurs at a position that is not conserved and is located within the Kinase domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Asp2785Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000198515 SCV000254155 uncertain significance Ataxia-telangiectasia syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 2785 of the ATM protein (p.Asp2785Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs587782417, ExAC 0.001%). This variant has been reported in a single control individual (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 142378). 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 asparagine 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, this variant has uncertain impact on ATM function. 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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