ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8987+3G>A (rs56360226)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163760 SCV000214338 likely benign Hereditary cancer-predisposing syndrome 2020-01-03 criteria provided, single submitter clinical testing In silico models in agreement (benign);RNA Studies
Invitae RCV000233461 SCV000283100 likely benign Ataxia-telangiectasia syndrome 2020-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725914 SCV000340486 uncertain significance not provided 2016-03-14 criteria provided, single submitter clinical testing
GeneDx RCV000725914 SCV000529088 likely benign not provided 2019-11-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163760 SCV000910973 likely benign Hereditary cancer-predisposing syndrome 2016-04-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000725914 SCV001143128 benign not provided 2018-09-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000318833 SCV001774525 benign not specified 2021-07-18 criteria provided, single submitter clinical testing Variant summary: ATM c.8987+3G>A 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251390 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 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 East Asian origin. To our knowledge, no occurrence of c.8987+3G>A in individuals affected with Breast Cancer/Ataxia Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Seven 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; benign, n=1, VUS, n=2). Based on the majority consensus among peers and the additional evidence outlined above, the variant was classified as benign.
Natera, Inc. RCV000233461 SCV001457204 uncertain significance Ataxia-telangiectasia syndrome 2020-01-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357667 SCV001553197 uncertain significance Familial ovarian cancer no assertion criteria provided clinical testing The ATM c.8987+3G>A variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs56360226) as "With other allele", ClinVar (classified as likely benign by GeneDx; as uncertain significance by Invitae, Ambry Genetics and one clinical laboratory). The variant was identified in control databases in 29 of 246148 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 5482 chromosomes (freq: 0.0004), East Asian in 27 of 17246 chromosomes (freq: 0.002); it was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The c.8987+3G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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