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 2017-08-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000164063 SCV000911566 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing
GeneDx RCV000219263 SCV000278813 uncertain significance not provided 2017-11-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.2074C>T at the cDNA level, p.Arg692Cys (R692C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in at least two individuals with a personal history of breast cancer (Caminsky 2016, Decker 2017). ATM Arg692Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg692Cys is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Arg692Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000168071 SCV000218725 uncertain significance Ataxia-telangiectasia syndrome 2018-10-21 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 not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 184752). 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.

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