ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5753G>C (p.Arg1918Thr) (rs148064985)

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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 RCV000131724 SCV000186764 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Athena Diagnostics Inc RCV000587454 SCV000840945 uncertain significance not provided 2017-11-01 criteria provided, single submitter clinical testing
Color RCV000131724 SCV000682285 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing
GeneDx RCV000587454 SCV000567304 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.5753G>C at the cDNA level, p.Arg1918Thr (R1918T) at the protein level, and results in the change of an Arginine to a Threonine (AGA>ACA). This variant has been observed in at least two individuals with breast cancer and one individual with non-Hodgkin lymphoma (Sipahimalani 2007, Bernstein 2010, Decker 2017). ATM Arg1918Thr was observed at an allele frequency of 0.01% (12/111,494) in individuals of European ancestry in large population cohorts (Lek 2016). ATM Arg1918Thr is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Arg1918Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587454 SCV000694307 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing Variant summary: The ATM c.5753G>C variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Threonine (T). 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 8/118416 control chromosomes at a frequency of 0.0000676, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant was observed in patients with breast cancer (Bernstein_JNCI_2010), non-Hodgin lymphoma (Sipahimalani_IJC_2007) and multiple adenomas (Weren_NG_2015), without strong evidence for pathogenicity. To our knowledge, in vitro/vivo studies assessing the functional impact of the variant have not been published at the time of scoring. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more clinical and functional data become available.
Invitae RCV000199373 SCV000254124 uncertain significance Ataxia-telangiectasia syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 1918 of the ATM protein (p.Arg1918Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is present in population databases (rs148064985, ExAC 0.01%). This variant has been reported in an individual with breast cancer (PMID: 20305132). It has also been reported in an individual with non-Hodgkin lymphoma (NHL), but evaluation of germline ATM variants in the heterozygous state and NHL shows no definitive association (PMID: 17640065, 26662178). ClinVar contains an entry for this variant (Variation ID: 142535). 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, 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 RCV000199373 SCV000838557 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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