ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.241A>G (p.Asn81Asp) (rs758962678)

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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 RCV000166809 SCV000217623 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000166809 SCV000687385 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing
GeneDx RCV000482292 SCV000570892 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.241A>G at the cDNA level, p.Asn81Asp (N81D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). Fernandes et al. (2005) examined the effect of this variant, in combination with three other missense variants, on cell survival, kinase activity and protein binding in vitro. However, the effect of ATM Asn81Asp on protein function has not been studied independently. ATM Asn81Asp was observed at an allele frequency of 0.05% (16/33,528) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Asn81Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000457539 SCV000546942 uncertain significance Ataxia-telangiectasia syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 81 of the ATM protein (p.Asn81Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs758962678, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 187119). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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