ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1671G>A (p.Met557Ile) (rs730881341)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159684 SCV000209689 uncertain significance not provided 2015-10-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.1671G>A at the cDNA level, p.Met557Ile (M557I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Met557Ile 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 Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Met557Ile occurs at a position that is not conserved and is not located in a functional domain (UniProt, Tavtigian 2009, Stracker 2013). 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 Met557Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000219319 SCV000275208 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-10 criteria provided, single submitter clinical testing
Invitae RCV000532840 SCV000622277 uncertain significance Ataxia-telangiectasia syndrome 2017-06-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 557 of the ATM protein (p.Met557Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181919). 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 isoleucine 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, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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