ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6257A>T (p.Tyr2086Phe) (rs730881380)

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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 RCV000568069 SCV000665456 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000568069 SCV000682319 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000159745 SCV000209760 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.6257A>T at the cDNA level, p.Tyr2086Phe (Y2086F) at the protein level, and results in the change of a Tyrosine to a Phenylalanine (TAT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr2086Phe was not observed at a significant allele frequency 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 Tyr2086Phe is located in the FAT domain (Stracker 2013). 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 Tyr2086Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000231734 SCV000283011 uncertain significance Ataxia-telangiectasia syndrome 2018-07-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 2086 of the ATM protein (p.Tyr2086Phe). The tyrosine residue is weakly conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181977). 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. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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