ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4666T>C (p.Tyr1556His) (rs587781320)

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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 RCV000129059 SCV000183759 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
GeneDx RCV000587733 SCV000569103 uncertain significance not provided 2016-09-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.4666T>C at the cDNA level, p.Tyr1556His (Y1556H) 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 Tyr1556His 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 Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr1556His 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 evidence, it is unclear whether ATM Tyr1556His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000530097 SCV000622521 uncertain significance Ataxia-telangiectasia syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 1556 of the ATM protein (p.Tyr1556His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs587781320, ExAC 0.002%) but has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 140851). 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.
Integrated Genetics/Laboratory Corporation of America RCV000587733 SCV000694287 uncertain significance not provided 2017-08-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.4666T>C (p.Tyr1556His) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/119682 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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