ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5005+7_5005+8del (rs587780626)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122857 SCV000166115 benign Ataxia-telangiectasia syndrome 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000159619 SCV000209604 benign Hereditary cancer-predisposing syndrome 2014-10-01 criteria provided, single submitter clinical testing The variant is found in BR-OV-HEREDIC,HEREDICANCER panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000122857 SCV000367058 uncertain significance Ataxia-telangiectasia syndrome 2016-06-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000501211 SCV000593484 likely benign not specified 2016-06-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000159619 SCV000682238 likely benign Hereditary cancer-predisposing syndrome 2015-04-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501211 SCV000916547 benign not specified 2019-09-20 criteria provided, single submitter clinical testing Variant summary: ATM c.5005+7_5005+8delTA 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00028 in 250464 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.3 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 South Asian origin. To our knowledge, no occurrence of c.5005+7_5005+8delTA in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four classified as likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001531758 SCV001747029 likely benign not provided 2021-02-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000501211 SCV001879496 benign not specified 2021-05-07 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000159619 SCV000787869 likely benign Hereditary cancer-predisposing syndrome 2017-06-21 no assertion criteria provided clinical testing
Natera, Inc. RCV000122857 SCV001462152 likely benign Ataxia-telangiectasia syndrome 2019-11-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354127 SCV001548667 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM c.5005+7_5005+8delTA variant was not identified in the literature nor was it identified in the GeneInsight-COGR, MutDB, LOVD 3.0, databases. The variant was also identified in dbSNP (ID: rs587780626) “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity: submitters: benign by GeneDx, likely benign by Invitae, Illumina Clinical Services Laboratory, Genetic Services Laboratory (University of Chicago) and Color Genomics Inc.), Clinvitae (3X), and in 68 (1 homozygous) of 276222 control chromosomes (frequency: 0.0002) the Genome Aggregation Database (Feb 27, 2017). Breakdown of observations by population are: South Asian in 40 (1 homozygous) of 30774 chromosomes (frequency: 0.001), Ashkenazi Jewish in 10 of 10126 chromosomes (frequency: 0.001), Other in 2 of 6442 chromosomes (frequency: 0.0003), European (Non-Finnish) in 15 of 125944 chromosomes (frequency: 0.0001), and Latino in 1 of 34388 chromosomes (frequency: 0.00003), while not observed in the African, East Asian and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of 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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