ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7291A>G (p.Lys2431Glu) (rs864622563)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204539 SCV000261127 uncertain significance Ataxia-telangiectasia syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 2431 of the ATM protein (p.Lys2431Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 12935922). ClinVar contains an entry for this variant (Variation ID: 220522). 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. 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.
GeneDx RCV000523242 SCV000617373 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.7291A>G at the cDNA level, p.Lys2431Glu (K2431E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has been observed in individuals with breast cancer and was absent in controls (Sommer 2003, Tavtigian 2009, Tung 2015, Decker 2017). ATM Lys2431Glu was not observed in large population cohorts (Lek 2016). This variant is located in the FAT 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 Lys2431Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563930 SCV000660509 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Counsyl RCV000204539 SCV000792419 uncertain significance Ataxia-telangiectasia syndrome 2017-06-23 criteria provided, single submitter clinical testing
Color RCV000563930 SCV000903691 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing

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