ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8671+9T>G (rs200190537)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000123717 SCV000167060 benign not specified 2014-02-10 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 RCV000988738 SCV000252989 likely benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000448274 SCV000537424 likely benign Hereditary cancer-predisposing syndrome 2015-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000123717 SCV000694383 likely benign not specified 2019-12-09 criteria provided, single submitter clinical testing Variant summary: ATM c.8671+9T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict no significant impact on normal splicing while two predict the variant strengthens an alternate cryptic intronic 5' donor site located position c.8671+4 in the gene sequence. However, any in-vivo consequences of these predictions have yet to be confirmed and/or reported by functional studies. The variant allele was found at a frequency of 0.00012 in 249426 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00012 vs 0.004), allowing no conclusion about variant significance. c.8671+9T>G has been reported in the literature in at-least one individual with 11q CLL (Skowronska_2012). This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or breast/CLL cancers. 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 without evidence for independent evaluation. All laboratories classified the variant as likely benign while on laboratory has retained the classification of this variant as benign prior to 2014. Based on the evidence outlined above and no emerging evidence supporting a pathognomic outcome for this variant in its evaluations spanning four years of testing at our laboratory, the variant was re-classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000589757 SCV000805630 likely benign not provided 2017-07-31 criteria provided, single submitter clinical testing
Mendelics RCV000988738 SCV001138584 likely benign Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000988738 SCV001264809 uncertain significance Ataxia-telangiectasia syndrome 2018-03-30 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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