ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2074C>T (p.Arg692Cys) (rs765965513)

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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 RCV000164063 SCV000214673 likely benign Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000168071 SCV000218725 uncertain significance Ataxia-telangiectasia syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 692 of the ATM protein (p.Arg692Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs765965513, ExAC 0.002%). This variant has been observed in individuals at risk for hereditary breast and/or ovarian cancer as well as in unaffected controls (PMID: 28652578, 26898890). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000219263 SCV000278813 uncertain significance not provided 2019-06-05 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function Observed in individuals with a personal history of breast cancer (Caminsky 2016, Decker 2017) This variant is associated with the following publications: (PMID: 28652578, 28779002, 27499925, 26898890)
Color Health, Inc RCV000164063 SCV000911566 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780902 SCV000918538 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: ATM c.2074C>T (p.Arg692Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246110 control chromosomes. This frequency is lower than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.1e-06 vs 0.004), allowing no conclusion about variant significance. c.2074C>T has been reported in the literature in an individual affected with breast cancer (Caminsky 2016). This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting classifications, 2 calling it a VUS and 1 calling it a Likely Benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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