ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2192A>T (p.Tyr731Phe) (rs730881345)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159690 SCV000209696 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.2192A>T at the cDNA level, p.Tyr731Phe (Y731F) at the protein level, and results in the change of a Tyrosine to a Phenylalanine (TAC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr731Phe was not observed in large population cohorts (Lek 2016). Since Tyrosine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr731Phe is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Tyr731Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000462835 SCV000546711 uncertain significance Ataxia-telangiectasia syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 731 of the ATM protein (p.Tyr731Phe). The tyrosine residue is moderately conserved and there is a small physicochemical difference between tyrosine and phenylalanine. 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: 181925). 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 phenylalanine 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.
Ambry Genetics RCV000568629 SCV000668067 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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