ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1066-6T>G (rs201686625)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000200968 SCV000602558 benign not specified 2016-07-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115132 SCV000183798 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000488246 SCV000840913 benign not provided 2018-08-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488246 SCV000574904 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing
Color RCV000115132 SCV000687286 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000003178 SCV000732989 likely benign Ataxia-telangiectasia syndrome no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000488246 SCV000232903 uncertain significance not provided 2014-09-16 criteria provided, single submitter clinical testing
GeneDx RCV000200968 SCV000149041 likely benign not specified 2017-11-20 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.
Genetic Services Laboratory, University of Chicago RCV000200968 SCV000593476 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000003178 SCV000743720 likely benign Ataxia-telangiectasia syndrome 2014-10-09 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000003178 SCV000745805 likely benign Ataxia-telangiectasia syndrome 2017-02-10 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000488246 SCV000694169 uncertain significance not provided 2017-08-29 criteria provided, single submitter clinical testing Variant summary:The ATM c.1066-6T>G variant involves the alteration of a conserved intronic nucleotide. 3/5 splice prediction tools predict no significant impact on normal splicing. Multiple in-vitro studies demonstrate a leaky" effect on splicing via skipping of exon 11. Functional studies have reported conflicting results for the effect of this variant on ATM kinase activity in vitro (Cheneviz-Trench_2002). The variant has been reported in multiple Ataxia Telangiectasia (A-T) patients in literature. In particular much focus has been placed on the patient identified in the Dork_2001, who was a 10 y/o boy diagnosed with A-T and found to be homozygous for the variant. However, Tavtigian_2009 reported that this patient carried second-site mutations that are sufficient to explain the A-T phenotype. Multiple functional studies utilized the cell line obtained from the patient reported by Dork_2001 in whom second-site mutations were identified; therefore, the functional effects reported in these studies need to be cautiously considered. Austen_2008 reported two brothers aged 48 and 50, one diagnosed with multiple myeloma and the other with child onset ataxia with AML, both carried the variant in opposite allele with another ATM variant R3008C. The authors speculate that the leaky splicing effect of this variant might have resulted in a milder AT phenotype. However, since the goal of this study was to investigate the occurrence of ATM mutations in patients with multiple myeloma, an unequivocal diagnosis of A-T in this study population cannot be assured. In addition, multiple publications cite the variant being found in breast cancer patients, with conflicting findings, i.e. segregating with disease in one family but lack of cosegregation in another family (Chenevix-Trench_2002). In addition, case-control studies and a meta-analysis show that this variant does not confer an increased risk for breast cancer (Ding_2011 and Bernstein_2006). This variant was found in 159/115732 control chromosomes (1 homozygote) from ExAC and literature at a frequency of 0.0013739 which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant for A-T (0.0039528). Moreover, reputable databases/clinical laboratories report the variant with conflicting classifications, from VUS (4), likely benign (1) to benign (1). Taking all the lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)" for Ataxia Telangiectasia until additionally information is available.
Invitae RCV000003178 SCV000153826 benign Ataxia-telangiectasia syndrome 2018-01-10 criteria provided, single submitter clinical testing
Mendelics RCV000003178 SCV000838482 likely benign Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000003178 SCV000023336 uncertain significance Ataxia-telangiectasia syndrome 2006-11-01 no assertion criteria provided literature only
PreventionGenetics RCV000200968 SCV000805489 benign not specified 2017-02-27 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115132 SCV000787840 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-14 no assertion criteria provided clinical testing

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