Submissions for variant NM_000051.4(ATM):c.1139_1142dup (p.Ser381fs)

gnomAD frequency: 0.00001  dbSNP: rs886041340

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000285085	SCV000329804	pathogenic	not provided	2023-07-12	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 a 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 1141insGACA; This variant is associated with the following publications: (PMID: 8659541, 8808599, 29922827, 30322717, 33510405, 34153142, 34570182, 9711876, 10817650, 9872980)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475637	SCV000546710	pathogenic	Ataxia-telangiectasia syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser381Argfs*27) 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). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9872980). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 280044). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000493506	SCV000581441	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-07	criteria provided, single submitter	clinical testing	The c.1139_1142dupACAG pathogenic mutation, located in coding exon 8 of the ATM gene, results from a duplication of ACAG at nucleotide position 1139, causing a translational frameshift with a predicted alternate stop codon (p.S381Rfs*27). This mutation has been detected in the compound heterozygous state with a second ATM mutation in individuals with ataxia telangiectasia (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Hacia JG et al. Genome Res. 1998 Dec;8:1245-58). Of note, this alteration is also designated as 1141insGACA in the published literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000475637	SCV000694172	pathogenic	Ataxia-telangiectasia syndrome	2016-08-24	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.1139_1142dupACAG (p.Ser381Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp393X, p.Gln1017X, p.Arg1466X, p.Tyr2755fs). One in silico tool predicts a damaging outcome for this variant. This variant was absent in 121144 control chromosomes, but has been cited in at least one AT patients in the literature. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000493506	SCV001357904	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 9 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. This variant is also known as 1141insGACA in the literature. This variant has been observed compound heterozygous in individuals affected with ataxia-telangiectasia (PMID: 9711876, 9872980, 10817650). This variant has been identified in 2/251284 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.
Genetic Services Laboratory, University of Chicago	RCV000285085	SCV002064358	pathogenic	not provided	2017-08-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500968	SCV002811045	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-09-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469213	SCV004209527	pathogenic	Familial cancer of breast	2023-11-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469213	SCV004932617	pathogenic	Familial cancer of breast	2024-01-12	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.	RCV000475637	SCV002092746	pathogenic	Ataxia-telangiectasia syndrome	2020-05-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739650	SCV005366629	pathogenic	ATM-related disorder	2024-07-24	no assertion criteria provided	clinical testing	The ATM c.1139_1142dupACAG variant is predicted to result in a frameshift and premature protein termination (p.Ser381Argfs*27). This variant has been reported in patients to be causative for autosomal recessive ataxia telangiectasia (reported as 1141isGACA in Hacia et al. 1998. PubMed ID: 9872980; Li et al. 2000. PubMed ID: 10817650) and has also been reported in a patient with ovarian cancer (Carter et al. 2018.PubMed ID: 30322717). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/280044/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.