ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.670A>G (p.Lys224Glu) (rs145053092)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131698 SCV000186735 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000131698 SCV000682362 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587384 SCV000703935 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000587384 SCV000209679 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.670A>G at the cDNA level, p.Lys224Glu (K224E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant was observed in the compound heterozygous state with an ATM frameshift variant in a patient with ataxia-telangiectasia (Li 2000). ATM Lys224Glu has been reported in multiple individuals with breast cancer, but also in unaffected controls (Tavtigian 2009, Decker 2017, Kraus 2017). ATM Lys224Glu was observed at an allele frequency of 0.018% (23/126,432) in individuals of European (non-Finnish) ancestry in large population cohorts (Lek 2016). ATM Lys224Glu 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 Lys224Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000211951 SCV000593495 uncertain significance not specified 2016-07-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587384 SCV000694330 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing Variant summary: The ATM c.670A>G (p.Lys224Glu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 8/125992 control chromosomes at a frequency of 0.0000635, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant was reported in multiple affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more evidence become available.
Invitae RCV000205199 SCV000259665 uncertain significance Ataxia-telangiectasia syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 224 of the ATM protein (p.Lys224Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs145053092, ExAC 0.01%). This variant has been reported in an individual affected with ataxia-telangiectasia (A–T) with a second ATM deleterious variant (PMID: 10817650), individuals with breast cancer (PMID: 20305132, 26689913, 19781682, 27616075), an individual with leukemia (PMID: 26580448), and an unaffected control individual (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 142522). 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 C15"). 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.
PreventionGenetics RCV000587384 SCV000805607 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000205199 SCV000803585 uncertain significance Ataxia-telangiectasia syndrome 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Ataxia telangiectasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.

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