ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1066-6T>G (rs201686625)

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Total submissions: 20
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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 RCV000003178 SCV000153826 benign Ataxia-telangiectasia syndrome 2020-12-04 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 2020-06-01 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 RCV001283462 SCV000602558 benign none provided 2020-03-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115132 SCV000687286 benign Hereditary cancer-predisposing syndrome 2020-12-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Illumina Clinical Services Laboratory,Illumina RCV000003178 SCV001263699 uncertain significance Ataxia-telangiectasia syndrome 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253153 SCV001428726 uncertain significance Familial cancer of breast 2019-06-13 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355481 SCV001550381 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM c.1066-6T>G variant was identified in 51 of 18,694 proband chromosomes (frequency: 0.003) from individuals or families with chronic lymphocatic leukemia, breast or ovarian cancer and was present in 70 of 27,754 control chromosomes (frequency: 0.003) from healthy individuals (Ding 2010, Tiao 2017). The variant was identified in dbSNP (rs201686625) as “with other allele”, ClinVar (classified as uncertain significance by Ambry Genetics, Integrated Genetics and 5 other submitters; as benign by Invitae, Color, Athena Diagnostics and 2 other submitters; and as likely benign by GeneDx and 2 other submitters) and LOVD 3.0 (observed 8x). The variant was identified in control databases in 357 of 266,346 chromosomes (2 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 23,658 chromosomes (freq: 0.0003), Other in 2 of 6198 chromosomes (freq: 0.0003), Latino in 19 of 32,652 chromosomes (freq: 0.0006), European in 286 of 123,010 chromosomes (freq: 0.002), Finnish in 18 of 25,254 chromosomes (freq: 0.0007), and South Asian in 25 of 27,738 chromosomes (freq: 0.0009); it was not observed in the Ashkenazi Jewish or East Asian populations. The variant was identified by our laboratory in multiple patients with pathogenic variants in BRCA2 (including c.1929del, p.Arg645Glufs*15 and c.755_758del, p.Asp252Valfs*24). The variant was also identified in the homozygous state in a patient with ataxia telangiectasia (Dork 2001), for whom alternate pathogenic variants were subsequently identified (Tavtigian 2009). A patient with mild ataxia telangiectasia was found to carry this variant in the compound heterozygous state and had reduced ATM protein expression and kinase activity, indicating this variant does not fully abolish protein expression and function (Austen 2016). Additionally, this variant leads to an increase in exon 11 skipping, although some exon 11 skipping is found in controls who do not carry this variant (Soukupova 2007). The c.1066-6T>G variant is located in the 3' splice region and does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence; variants involving these positions sometimes affect splicing and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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