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
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.
Invitae RCV000488246 SCV000153826 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115132 SCV000183798 likely benign Hereditary cancer-predisposing syndrome 2019-05-09 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000488246 SCV000232903 uncertain significance not provided 2014-09-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488246 SCV000574904 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000200968 SCV000593476 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000003178 SCV000602558 benign Ataxia-telangiectasia syndrome 2018-08-20 criteria provided, single submitter clinical testing
Color RCV000115132 SCV000687286 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000200968 SCV000694169 benign not specified 2019-06-07 criteria provided, single submitter clinical testing Variant summary: ATM c.1066-6T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. Although the variant was reported to be associated with a partial splicing defect (see e.g. Broeks_2000, Dork_2001, Fang_2010), several patient samples were also reported to have second-site mutations that could also affect splicing, therefor the splicing effect of the variant in isolation is currently unclear (Tavtigian_2009, Fievet_2019). The variant allele was found at a frequency of 0.0014 in 270694 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.0024 in the gnomAD database (including 2 homozygotes). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, the variant was reported to be found in the FLOSSIES database in 33/7325 European American women, who were older than age 70 years and have never had cancer. The allele frequency in this cohort is also higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0023 vs. 0.001), further supporting a benign role for the variant. Though the variant has been reported in the literature in homozygous individuals affected with Ataxia Telangiectasia (A-T), these patients carried second-site mutations that were sufficient to explain the A-T phenotype (Tavtigian_2009, Fievet_2019). The variant was also reported in compound heterozygosity, with (potential) pathogenic ATM variants in trans, in an individual affected with breast cancer (Fang_2010) and also in a patient with multiple myeloma and (per authors) an atypical, milder A-T phenotype (Austen_2008). Therefore these reports do not support the association of the variant with A-T. The variant, c.1066-6T>G, also has been reported in the literature in individuals affected with Breast Cancer, however in most of the cases co-occurrence and/or co-segregation data was not provided, therefore these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Moreover, in case-control studies the variant did not have significantly increased risk association with breast cancer (Dork_2001, Bernstein_2006, Ding_2011). One recent case-control study reported the variant with an increased risk for CLL (OR: 3.29), however this analysis had a relatively small sample size and most patients were sporadic cases, thus this risk association might not be reliable (Tiao 2017). Twelve other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as VUS (4x), likely benign (3x) / benign (5x). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000003178 SCV000743720 likely benign Ataxia-telangiectasia syndrome 2014-10-09 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000200968 SCV000805489 benign not specified 2017-02-27 criteria provided, single submitter clinical testing
Mendelics RCV000003178 SCV000838482 likely benign Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000488246 SCV000840913 benign not provided 2018-08-20 criteria provided, single submitter clinical testing
OMIM RCV000003178 SCV000023336 uncertain significance Ataxia-telangiectasia syndrome 2006-11-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000003178 SCV000732989 likely benign Ataxia-telangiectasia syndrome no assertion criteria provided 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
True Health Diagnostics RCV000115132 SCV000787840 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-14 no assertion criteria provided clinical testing

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