ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6115G>A (p.Glu2039Lys) (rs864622251)

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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 RCV000574550 SCV000667845 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Insufficient evidence
Color RCV000574550 SCV000908453 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
GeneDx RCV000255601 SCV000322164 likely pathogenic not provided 2015-09-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.6115G>A at the cDNA level, p.Glu2039Lys (E2039K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed, in a large meta-analysis, in 1/2531 breast cancer cases and 0/2245 controls (Tavtigian 2009). This variant has also been observed in the compound heterozygous state in an individual with Ataxia-telangiectasia and was shown to have reduced kinase activity compared to wild type (Barone 2009, Jacquemin 2012). ATM Glu2039Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Glu2039Lys occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available information, we consider ATM Glu2039Lys to be a likely pathogenic variant.
Invitae RCV000204272 SCV000259858 likely pathogenic Ataxia-telangiectasia syndrome 2018-02-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2039 of the ATM protein (p.Glu2039Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 19781682), as well as several individuals with early-onset breast cancer (Invitae database). It has also been reported in 2 individuals affected with ataxia-telangiectasia (A-T) (PMID: 22071889, Invitae database). In one of the A-T affected individuals this variant occurred with another ATM variant, while the second individual was homozygous for this variant. ClinVar contains an entry for this variant (Variation ID: 219787). An experimental study using a patient-derived lymphoblast cell line has shown that while this missense change results in the production of a stable ATM protein that demonstrates normal localization to the nucleus, the cells are defective in responding to ionizing radiation (PMID: 22071889). A second study showed that this missense variant causes reduced ATM kinase activity (PMID: 19431188). In summary, this variant is a rare missense change that has been reported in affected individuals and shown to disrupt protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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