Submissions for variant NM_000051.4(ATM):c.6997dup

gnomAD frequency: 0.00001  dbSNP: rs587781299

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221494	SCV002499294	pathogenic	Familial cancer of breast	2022-03-16	reviewed by expert panel	curation	The ATM c.6997dupA (p.Thr2333Nfs*40) variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a compound heterozygous state (presumed) or with a second variant unidentified in four individuals with Ataxia-Telangiectasia (PMID 21459046, 10817650, 9463314, Clinical Laboratory Data: PM3_Strong). Variant is absent in the GnomAD v2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel
Ambry Genetics	RCV000129007	SCV000172903	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-13	criteria provided, single submitter	clinical testing	The c.6997dupA pathogenic mutation, located in coding exon 47 of the ATM gene, results from a duplication of A at nucleotide position 6997, causing a translational frameshift with a predicted alternate stop codon (p.T2333Nfs*40). This mutation has been reported in multiple individuals with ataxia-telangiectasia (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Exley AR et al. Clin. Immunol. 2011 Jul;140:26-36; Mandola AB et al. Front Immunol, 2019 Dec;10:2940). It has also been reported patients with personal and/or family histories of early onset breast cancer, ovarian cancer and prostate cancer (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; Tung N et al. Cancer, 2015 Jan;121:25-33; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000205392	SCV000260039	pathogenic	Ataxia-telangiectasia syndrome	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr2333Asnfs*40) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with colorectal cancer and breast cancer and ataxia-telangiectasia (PMID: 9463314, 21787400, 23585368, 26845104). ClinVar contains an entry for this variant (Variation ID: 140818). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129007	SCV000266020	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000236518	SCV000292478	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6996_6997insA; 6997_6998insA; This variant is associated with the following publications: (PMID: 25186627, 16832357, 15928302, 21787400, 23585368, 26845104, 9463314, 27153395, 28152038, 21459046, 10817650, 19781682, 29625052, 31921190, 30322717, 28888541, 32866655, 33436325, 29922827, 32471518, 35047863, 26896183, 33804961, 23807571, 25614872)
Counsyl	RCV000205392	SCV000678163	likely pathogenic	Ataxia-telangiectasia syndrome	2015-08-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129007	SCV000682383	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 48 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 9463314, 10817650, 15928302). This variant has also been reported in individuals affected with breast cancer and ovarian cancer (PMID: 25186627, 26845104, 30322717). This variant has been identified in 2/245820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000205392	SCV000916577	pathogenic	Ataxia-telangiectasia syndrome	2018-06-04	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6997dupA (p.Thr2333AsnfsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 245820 control chromosomes. c.6997dupA has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Stankovic 1998, Li 2000, Exley 2011). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating the lack of ATM protein and ATM kinase activity in LCLs derived from a patient who had the variant of interest in compound heterozygosity with an other truncating ATM variant (Exley 2011). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (5x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics	RCV000236518	SCV000927694	pathogenic	not provided	2018-05-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000236518	SCV001475569	pathogenic	not provided	2020-03-18	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Revvity Omics, Revvity	RCV000205392	SCV002020826	pathogenic	Ataxia-telangiectasia syndrome	2022-02-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498639	SCV002813444	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-08-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002221494	SCV004204311	pathogenic	Familial cancer of breast	2024-02-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236518	SCV004222079	pathogenic	not provided	2020-03-18	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the ATM mRNA and causes the premature termination of ATM protein synthesis. In the published literature, the variant has been reported in patients with ataxia-telangiectasia (PMIDs: 31921190 (2019), 15928302 (2005), 9463314 (1998)), and breast and/or ovarian cancer (PMIDs: 30322717 (2018), 27153395 (2016), 25186627 (2015), 21787400 (2011), 19781682 (2009)). Based on the available information, this variant is classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236518	SCV004242543	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002221494	SCV004931138	pathogenic	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000205392	SCV002080064	pathogenic	Ataxia-telangiectasia syndrome	2020-10-20	no assertion criteria provided	clinical testing