ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3257G>A (p.Arg1086His) (rs769857066)

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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 RCV000575194 SCV000660457 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000575194 SCV000908263 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000213977 SCV000278819 uncertain significance not provided 2018-09-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.3257G>A at the cDNA level, p.Arg1086His (R1086H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been reported in an individual with chronic lymphocytic leukemia and in an individual with head and neck squamous cell carcinoma (Lu 2015, Tiao 2017). ATM Arg1086His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the beta-adaptin interaction region (Tavtigian 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg1086His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000234243 SCV000282926 uncertain significance Ataxia-telangiectasia syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1086 of the ATM protein (p.Arg1086His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs769857066, ExAC 0.02%). This variant has been reported in an individual affected with head and neck squamous cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 234265). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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