ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8968G>A (p.Glu2990Lys) (rs1800558)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212095 SCV000149181 uncertain significance not provided 2018-05-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.8968G>A at the cDNA level, p.Glu2990Lys (E2990K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in an individual undergoing multi-gene hereditary cancer panel testing due to a history of a Lynch-related cancer and/or polyps who also harbored a reportedly pathogenic MSH6 variant (Yurgelun 2015). This variant was also observed in normal tissue samples from individuals with acute myeloid leukemia, breast cancer, and ovarian cancer (Lu 2015). ATM Glu2990Lys was observed at an allele frequency of 0.11% (11/10,150) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located in the FATC domain (Stracker 2013). 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 Glu2990Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115272 SCV000186450 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000200530 SCV000254159 uncertain significance Ataxia-telangiectasia syndrome 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2990 of the ATM protein (p.Glu2990Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs1800558, ExAC 0.007%). This variant has been reported in individuals affected with breast cancer, ovarian cancer, acute myeloid leukemia and prostate cancer (PMID: 26689913, 29368341). ClinVar contains an entry for this variant (Variation ID: 127466). 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.
Color RCV000115272 SCV000537525 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-17 criteria provided, single submitter clinical testing

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