ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6232T>C (p.Ser2078Pro) (rs587779854)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212042 SCV000149137 uncertain significance not provided 2016-06-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.6232T>C at the cDNA level, p.Ser2078Pro (S2078P) at the protein level, and results in the change of a Serine to a Proline (TCC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ser2078Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ser2078Pro occurs at a position that is conserved in mammals and is located in the FAT 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 Ser2078Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115228 SCV000216076 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000556775 SCV000622652 uncertain significance Ataxia-telangiectasia syndrome 2018-03-20 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 2078 of the ATM protein (p.Ser2078Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs587779854, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127423). 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: "Deleterious"; PolyPhen-2: "Benign"; 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.
Color RCV000115228 SCV000905229 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing

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