ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5189G>A (p.Arg1730Gln) (rs373789346)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212028 SCV000149116 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.5189G>A at the cDNA level, p.Arg1730Gln (R1730Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was observed in an individual with chronic lymphocytic leukemia and in several unaffected controls (Tiao 2017). ATM Arg1730Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Arg1730Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115207 SCV000217480 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Invitae RCV000197381 SCV000254120 uncertain significance Ataxia-telangiectasia syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1730 of the ATM protein (p.Arg1730Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs373789346, ExAC 0.006%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127402). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000115207 SCV000687609 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780913 SCV000918559 uncertain significance not specified 2019-07-05 criteria provided, single submitter clinical testing Variant summary: ATM c.5189G>A (p.Arg1730Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 298582 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5189G>A has been reported in the literature in individuals affected with different types of cancer including breast and ovarian (Chan_2018, Momozawa_2018, Tiao_2017, Jiang_2018), however without evidence for causality. Furthermore, the variant was reported in 1/7325 European American women, who are older than age 70 years, and who have never had cancer (in the FLOSSIES database). A large Japanese case-control study reported the variant in both cases and controls, with a p-value trending toward significance in association with breast cancer (Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000197381 SCV001138514 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing

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