ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1511A>G (p.Asn504Ser) (rs56365018)

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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 RCV000218923 SCV000275380 likely benign Hereditary cancer-predisposing syndrome 2017-05-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000218923 SCV000904442 likely benign Hereditary cancer-predisposing syndrome 2017-01-23 criteria provided, single submitter clinical testing
GeneDx RCV000486813 SCV000570155 uncertain significance not specified 2017-03-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.1511A>G at the cDNA level, p.Asn504Ser (N504S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asn504Ser was not observed at a significant allele frequency in 1000 Genomes. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. ATM Asn504Ser occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2010). 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 Asn504Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205555 SCV000260693 uncertain significance Ataxia-telangiectasia syndrome 2018-09-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 504 of the ATM protein (p.Asn504Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs56365018, ExAC 0.06%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 220272). 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 serine 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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