ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6101G>A (p.Arg2034Gln) (rs3218670)

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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 RCV000115223 SCV000216647 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115223 SCV000682307 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000212038 SCV000149132 uncertain significance not provided 2018-04-24 criteria provided, single submitter clinical testing This variant is denoted ATM c.6101G>A at the cDNA level, p.Arg2034Gln (R2034Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was absent among 4,112 cases but was observed in 1/2,399 controls in a breast cancer case-control meta-analysis by Tavtigian et al. (2009). ATM Arg2034Gln was observed at an allele frequency of 0.074% (14/18,836) in individuals of East Asian ancestry in large population cohorts (Lek 2016). ATM Arg2034Gln 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 Arg2034Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000457673 SCV000547051 uncertain significance Ataxia-telangiectasia syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2034 of the ATM protein (p.Arg2034Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs3218670, ExAC 0.07%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127418). 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.

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