ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.749G>A (p.Arg250Gln) (rs56123940)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129173 SCV000183906 likely benign Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000211952 SCV000209681 likely benign not specified 2018-03-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000204231 SCV000259752 likely benign Ataxia-telangiectasia syndrome 2019-12-30 criteria provided, single submitter clinical testing
Counsyl RCV000204231 SCV000799869 uncertain significance Ataxia-telangiectasia syndrome 2018-05-15 criteria provided, single submitter clinical testing
GeneKor MSA RCV000129173 SCV000821872 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000204231 SCV000838477 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000129173 SCV000910702 likely benign Hereditary cancer-predisposing syndrome 2015-08-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000211952 SCV001360414 uncertain significance not specified 2019-02-21 criteria provided, single submitter clinical testing Variant summary: ATM c.749G>A (p.Arg250Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 276694 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (5.1e-05 vs 0.004), allowing no conclusion about variant significance. However, the presence of a homozygous occurrence in healthy controls might still suggest that the variant is a benign polymorphism. c.749G>A has been reported in the literature in individuals affected with various tumor phenotypes (Greenman 2007, La Paglia 2009, Tung 2015, Tiao 2017, Martin-Morales 2018), however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with the disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (4 classifying it as VUS, and 2 as likely benign). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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