ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2635A>G (p.Ile879Val) (rs556598169)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159759 SCV000209778 uncertain significance not provided 2016-04-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.2635A>G at the cDNA level, p.Ile879Val (I879V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). ATM Ile879Val has been observed in an individual with non-Hodgkin lymphoma (Sipahimalani 2007). A large meta-analysis found this variant to be absent in breast cancer patients (0/2,531) but present in three control subjects (3/2,245) (Tavtigian 2009). ATM Ile879Val 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 Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Ile879Val 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 information, it is unclear whether ATM Ile879Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000469928 SCV000546738 uncertain significance Ataxia-telangiectasia syndrome 2017-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 879 of the ATM protein (p.Ile879Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs556598169, ExAC 0.01%). This variant has been reported in an individual affected with non-Hodgkin lymphoma  (PMID: 17640065) and in three unaffected control individuals in a breast cancer study (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 181990). 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 valine 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. 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.
Ambry Genetics RCV000568728 SCV000660699 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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