ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5747T>C (p.Met1916Thr) (rs1060501557)

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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 RCV000574580 SCV000667965 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000574580 SCV000682283 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
GeneDx RCV000482185 SCV000566461 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.5747T>C at the cDNA level, p.Met1916Thr (M1916T) 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 Met1916Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Met1916Thr 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, Stracker 2013). 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 Met1916Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000471247 SCV000546715 uncertain significance Ataxia-telangiectasia syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1916 of the ATM protein (p.Met1916Thr). The methionine residue is weakly 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: 407488). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). 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.

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