ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5488A>G (p.Met1830Val) (rs587781622)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129712 SCV000184515 likely benign Hereditary cancer-predisposing syndrome 2017-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Color RCV000129712 SCV000910899 likely benign Hereditary cancer-predisposing syndrome 2016-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000590655 SCV000292471 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.5488A>G at the cDNA level, p.Met1830Val (M1830V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant was observed in at least one individual with a personal history of breast cancer (Yehia 2018). ATM Met1830Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Met1830Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590655 SCV000694303 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The ATM c.5488A>G (p.Met1830Val) variant involves the alteration of a non-conserved nucleotide and 4/4 in silico tools (SNPsandGo not captured here due to low reliability index) predict a benign outcome. This variant was found in 2/121150 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). Multiple publications have cited the variant as an assumed somatic occurrence, however, information is limited. In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. 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.
Invitae RCV000199250 SCV000254121 uncertain significance Ataxia-telangiectasia syndrome 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1830 of the ATM protein (p.Met1830Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs587781622, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141271). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.

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