ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8860T>C (p.Tyr2954His) (rs371619067)

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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 RCV000215430 SCV000276999 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000456818 SCV000546719 uncertain significance Ataxia-telangiectasia syndrome 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 2954 of the ATM protein (p.Tyr2954His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs371619067, ExAC 0.002%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 232777). 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 disruptive, but 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.
GeneDx RCV000479457 SCV000567173 uncertain significance not provided 2015-07-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.8860T>C at the cDNA level, p.Tyr2954His (Y2954H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr2954His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr2954His occurs at a position that is conserved across species and is located in the PI3/PI4 Kinase domain (Stracker 2013, Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Tyr2954His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000215430 SCV000687858 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing

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