ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2425T>G (p.Ser809Ala) (rs926246315)

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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 RCV000563437 SCV000660578 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000563437 SCV000911958 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing
GeneDx RCV000481080 SCV000566624 uncertain significance not provided 2015-05-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.2425T>G at the cDNA level, p.Ser809Ala (S809A) at the protein level, and results in the change of a Serine to an Alanine (TCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ser809Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ser809Ala occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009, UniProt). 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 Ser809Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000704994 SCV000833971 uncertain significance Ataxia-telangiectasia syndrome 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 809 of the ATM protein (p.Ser809Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 419069). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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