ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6332A>G (p.His2111Arg) (rs876658300)

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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 RCV000223653 SCV000273340 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000226701 SCV000283012 uncertain significance Ataxia-telangiectasia syndrome 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 2111 of the ATM protein (p.His2111Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast and colon cancer (PMID: 12935922, 19781682, 10738255, 26976419). ClinVar contains an entry for this variant (Variation ID: 229957). 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 RCV000478549 SCV000568329 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.6332A>G at the cDNA level, p.His2111Arg (H2111R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has been observed in breast cancer patients, but was also observed in a cancer free control subject (Sommer 2003, Tavtigian 2009, Tung 2016, Decker 2017). ATM His2111Arg 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 His2111Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000223653 SCV000682325 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing
Counsyl RCV000226701 SCV000790020 uncertain significance Ataxia-telangiectasia syndrome 2017-03-13 criteria provided, single submitter clinical testing

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