ClinVar Miner

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

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Total submissions: 10
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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 RCV001704053 SCV000209681 likely benign not provided 2020-10-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19404735, 17344846, 22529920, 28779002, 31159747)
Invitae RCV000204231 SCV000259752 likely benign Ataxia-telangiectasia syndrome 2020-12-07 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 Health, Inc RCV000129173 SCV000910702 likely benign Hereditary cancer-predisposing syndrome 2015-08-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211952 SCV001360414 likely benign not specified 2021-07-17 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 4.8e-05 in 250992 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.8e-05 vs 0.004), allowing no conclusion about variant significance. However, the presence of a homozygous occurrence in healthy controls suggests that the variant has a neutral impact. c.749G>A has been reported in the literature in settings of multigene panel testing in individuals affected with various cancer phenotypes without strong evidence for causality (examples-Grennman_2007, LaPaglia_2009, Haiman_2013, Tung_2015, Muller_2015, Tiao_2017, Martin-Moales_2018, Tsaousis_2019, Weitzel_2019, Sandoval_2021). These report(s) do 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. Nine 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 (likely benign, n=4; VUS, n=4). Based on the emerging majority consensus among peers and the evidence outlined above, the variant was re-classified as likely benign.
Division of Medical Genetics, University of Washington RCV001257469 SCV001434275 uncertain significance Familial cancer of breast 2019-10-04 criteria provided, single submitter clinical testing This variant has been reported in the literature in an individual with breast cancer (Paglia 2010). This variant has an overall allele frequency of 0.00005 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Natera, Inc. RCV000204231 SCV001454847 likely benign Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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