ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1300C>T (p.Pro434Ser) (rs1064795171)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480809 SCV000570700 uncertain significance not provided 2016-06-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.1300C>T at the cDNA level, p.Pro434Ser (P434S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). This variant was observed in the peripheral blood of an individual with B-cell chronic lymphocytic leukemia, though germline status was not determined. While the sample from this individual demonstrated defective p21 and MDM2 up-regulation when subjected to ionizing radiation, it showed normal p53 accumulation and normal ATM protein expression (Stankovic 2002). ATM Pro434Ser 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 Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Pro434Ser occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). 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 Pro434Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570473 SCV000668142 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Invitae RCV000794458 SCV000933868 uncertain significance Ataxia-telangiectasia syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 434 of the ATM protein (p.Pro434Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. 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: 421484). 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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