Submissions for variant NM_000051.4(ATM):c.1027_1030del (p.Glu343fs)

dbSNP: rs587780612

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122816	SCV000166073	pathogenic	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu343Ilefs*2) 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 (rs587780612, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348, 10817650, 12552559, 18502988, 21792198, 22213089). This variant is also known as 1024delAAAG, 1027_1030delAAAG, and 1027del4. ClinVar contains an entry for this variant (Variation ID: 135731). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129901	SCV000184719	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-28	criteria provided, single submitter	clinical testing	The c.1027_1030delGAAA pathogenic mutation, located in coding exon 7 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 1027 to 1030, causing a translational frameshift with a predicted alternate stop codon (p.E343Ifs*2). This mutation has been reported in numerous patients with classic Ataxia-Telangiectasia (A-T) (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70(2):122-33; Buzin C et al. Hum. Mutat. 2003 Feb;21(2):123-31) and in an individual from a hereditary breast and ovarian cancer cohort (Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). ATM protein expression was found to be entirely absent in one A-T individual with this alteration in conjunction with another ATM mutation (Reiman A et al. Br. J. Cancer. 2011 Aug;105(4):586-91). Of note, this alteration is also designated as 1024delAAAG, c.1024_1027delAAAG, and 1027_1030delAAAG in 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.
Counsyl	RCV000122816	SCV000220152	likely pathogenic	Ataxia-telangiectasia syndrome	2014-03-10	criteria provided, single submitter	literature only
Vantari Genetics	RCV000129901	SCV000266988	pathogenic	Hereditary cancer-predisposing syndrome	2015-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000236560	SCV000293429	pathogenic	not provided	2023-05-05	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; Published functional studies demonstrate reduced levels of protein expression (Becker-Catania et al., 2000); This variant is associated with the following publications: (PMID: 22213089, 19535770, 18502988, 26270727, 28126470, 17985259, 28152038, 10330348, 12552559, 10817650, 21792198, 28873162, 30067863, 30267352, 29506128, 30716324, 29288088, 30980208, 30338439, 26689913, 31871297, 29625052, 29922827, 33858029, 10873394)
Color Diagnostics, LLC DBA Color Health	RCV000129901	SCV000681947	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 8 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. In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and 1/53460 controls (PMID: 33471991). This variant has been reported in individuals with ataxia-telangiectasia (PMID: 10330348, 10817650, 12552559) with several confirmed in the compound heterozygous state (PMID: 10873394, 21792198, 22213089). This variant has been identified in 8/251144 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	RCV000122816	SCV000694167	pathogenic	Ataxia-telangiectasia syndrome	2016-05-09	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.1027_1030delGAAA (p.Glu343Ilefs) 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). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121026 control chromosomes but has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Athena Diagnostics	RCV000236560	SCV000840912	pathogenic	not provided	2018-03-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000122816	SCV002020731	pathogenic	Ataxia-telangiectasia syndrome	2019-04-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129901	SCV002529674	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	curation
Baylor Genetics	RCV003460865	SCV004207078	pathogenic	Familial cancer of breast	2024-03-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236560	SCV004219899	pathogenic	not provided	2018-03-31	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Additionally, the variant was found in at least one symptomatic patient, and found in general population data at a frequency that is consistent with pathogenicity.
Myriad Genetics, Inc.	RCV003460865	SCV004932805	pathogenic	Familial cancer of breast	2024-01-11	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.	RCV000122816	SCV001456878	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000236560	SCV001977794	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000236560	SCV001977910	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739419	SCV005348326	pathogenic	ATM-related disorder	2024-07-11	no assertion criteria provided	clinical testing	The ATM c.1027_1030delGAAA variant is predicted to result in a frameshift and premature protein termination (p.Glu343Ilefs*2). This variant has previously been reported to be causative for autosomal recessive ataxia telangiectasia (see for example, Teraoka et al. 1999. PubMed ID: 10330348, reported as 1024del; Verhagen et al. 2009. PubMed ID: 19535770). This variant is also reported as pathogenic in an individual with adenocarcinoma of the gastroesophageal junction (Table 1. El Jabbour et al. 2022. PubMed ID: 35078243). This variant is reported in 0.050% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135731/?new_evidence=true). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.