ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3614G>A (p.Arg1205His) (rs769106895)

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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 RCV000569109 SCV000665259 likely benign Hereditary cancer-predisposing syndrome 2018-04-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000569109 SCV000903866 likely benign Hereditary cancer-predisposing syndrome 2016-04-08 criteria provided, single submitter clinical testing
GeneDx RCV000486877 SCV000569511 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.3614G>A at the cDNA level, p.Arg1205His (R1205H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in three individuals with breast cancer as well as in unaffected controls (Momozawa 2018). ATM Arg1205His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (Tavtigian 2009). 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 Arg1205His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000569109 SCV000821850 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000227875 SCV000282935 uncertain significance Ataxia-telangiectasia syndrome 2016-03-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1205 of the ATM protein (p.Arg1205His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs769106895, ExAC <0.01%) but has not been reported in the literature in individuals with a ATM-related disease. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, 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, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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