ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2258T>C (p.Met753Thr) (rs587781607)

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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 RCV000129691 SCV000184492 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient evidence
GeneDx RCV000482876 SCV000570486 uncertain significance not provided 2016-05-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.2258T>C at the cDNA level, p.Met753Thr (M753T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Met753Thr 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 Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Met753Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is not located in a known functional domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Met753Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000554034 SCV000622316 uncertain significance Ataxia-telangiectasia syndrome 2017-07-18 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 753 of the ATM protein (p.Met753Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141255). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780880 SCV000918506 uncertain significance not specified 2017-10-12 criteria provided, single submitter clinical testing Variant summary: The ATM c.2258T>C (p.Met753Thr) variant causes a missense change involving the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/30988 control chromosomes (gnomAD) at a frequency of 0.0000645, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). In addition, multiple clinical diagnostic laboratories 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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