ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2150G>C (p.Arg717Pro) (rs768874297)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479906 SCV000569088 uncertain significance not provided 2017-02-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.2150G>C at the cDNA level, p.Arg717Pro (R717P) at the protein level, and results in the change of an Arginine to a Proline (CGG>CCG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in an extrauterine Mullerian carcinoma (Ritterhouse 2016). ATM Arg717Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg717Pro occurs at a position that is not conserved and is not located in a known functional domain (Stracker 2013, Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Arg717Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000555903 SCV000622310 uncertain significance Ataxia-telangiectasia syndrome 2018-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 717 of the ATM protein (p.Arg717Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs768874297, ExAC 0.003%). This variant has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 420303). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
Ambry Genetics RCV000571648 SCV000660505 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000571648 SCV000911297 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779768 SCV000916556 uncertain significance not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: ATM c.2150G>C (p.Arg717Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 0.00001 in 276434 control chromsomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (1.4e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.2150G>C, has been reported in the literature in an individual diagnosed with a carcinoma (specific location was not indicated in publication from Ritterhouse_2016). This report does not provide an unequivocal conclusion about association of the variant with Ataxia-Telangiectasia. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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