ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.280A>G (p.Met94Val) (rs864622758)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222447 SCV000276795 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign)
Color RCV000222447 SCV000682080 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
GeneDx RCV000481117 SCV000564606 uncertain significance not specified 2016-11-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.280A>G at the cDNA level, p.Met94Val (M94V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been reported in an individual with a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015). ATM Met94Val 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 Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Met94Val occurs at a position that is conserved across species and is located in the p53 and BRCA1 interaction domain (Tavtigian 2009). Protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, while splicing prediction models predict that this variant may create a novel cryptic donor site upstream of the natural splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether ATM Met94Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000204864 SCV000262337 uncertain significance Ataxia-telangiectasia syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 94 of the ATM protein (p.Met94Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 221134). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, 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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