Submissions for variant NM_000051.4(ATM):c.5005+7_5005+8del

gnomAD frequency: 0.00009  dbSNP: rs587780626

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122857	SCV000166115	benign	Ataxia-telangiectasia syndrome	2024-01-31	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 Laboratory Services, 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 Diagnostics, LLC DBA Color Health	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 Center for Human Genetics Tuebingen	RCV001531758	SCV001747029	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ATM: BP4
Athena Diagnostics Inc	RCV000501211	SCV001879496	benign	not specified	2021-05-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798395	SCV002042264	likely benign	Breast and/or ovarian cancer	2021-05-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000501211	SCV002760578	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001531758	SCV004221146	benign	not provided	2021-05-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000159619	SCV004228067	likely benign	Hereditary cancer-predisposing syndrome	2023-12-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003965034	SCV004782600	likely benign	ATM-related condition	2019-09-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001531758	SCV001978170	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001531758	SCV001980002	likely benign	not provided		no assertion criteria provided	clinical testing