ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2336T>C (p.Met779Thr) (rs587778066)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567786 SCV000665170 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000567786 SCV000911220 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000627993 SCV000793303 uncertain significance Ataxia-telangiectasia syndrome 2017-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000657076 SCV000617367 uncertain significance not provided 2017-04-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.2336T>C at the cDNA level, p.Met779Thr (M779T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has been observed in at least two individuals with a personal history of breast cancer (Broeks 2008, Tavtigian 2009) and in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the Bodian study were younger than 50 years old; thus, the unaffected status of this individual may not be significant. ATM Met779Thr was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Met779Thr 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. 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 Met779Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120122 SCV000084260 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000627993 SCV000748880 uncertain significance Ataxia-telangiectasia syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 779 of the ATM protein (p.Met779Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs587778066, ExAC 0.006%). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 17393301, 19781682). ClinVar contains an entry for this variant (Variation ID: 133606). 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.
Mendelics RCV000627993 SCV000838503 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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