Submissions for variant NM_000051.4(ATM):c.3154-2A>G

gnomAD frequency: 0.00001  dbSNP: rs730881357

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211994	SCV000209718	pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Observed in individuals with pancreatic, ovarian, and other cancers (Lilyquist et al., 2017; Hu et al., 2018; Bertelsen et al., 2019; Kim et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS23-2A>G; This variant is associated with the following publications: (PMID: 27304073, 24422204, 26681312, 25561518, 14695534, 34426522, 29922827, 31263571, 28888541, 34308104, 10980530)
Ambry Genetics	RCV000159707	SCV000216964	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The c.3154-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 21 in the ATM gene. This mutation was identified in an ataxia-telangiectasia patient who carried a second ATM mutation in trans; RNA analysis showed that this mutation disrupts the native splice acceptor site, leading to the insertion of 14 nucleotides from intron 21 into the transcript, and causing a translational frameshift with a predicted alternate stop codon (Laake K et al. Hum. Mutat. 2000 Sep;16:232-46, Ambry internal data). Of note, this alteration is also designated as IVS23-2A>G in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206276	SCV000259237	pathogenic	Ataxia-telangiectasia syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 21 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with esophageal cancer and ataxia telangiectasia (PMID: 10980530, 31263571). 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: 181940). Studies have shown that disruption of this splice site results in activation of a cryptic splice site in intron 21 and introduces a premature termination codon (PMID: 24422204; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000206276	SCV000678117	pathogenic	Ataxia-telangiectasia syndrome	2017-05-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159707	SCV000905171	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 21 of the ATM gene. Functional RNA studies have shown that this variant causes an out-of-frame insertion of 14 nucleotides, resulting in a frameshift and premature stop signal (PMID:10980530, 24422204). This variant has been reported in the compound heterozygous state in two individuals affected with ataxia-telangiectasia (PMID:10980530, 24422204). This variant has also been reported in an individual affected with pancreatic cancer (PMID: 29922827) and an individual affected with gastroesophageal junction adenocarcinoma (PMID: 35078243). This variant has not been identified 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	RCV000206276	SCV001362663	pathogenic	Ataxia-telangiectasia syndrome	2019-10-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3154-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing as resulting in the insertion of 14 nucleotides from intron 21 into the transcript, causing a frameshift mutation that disrupts the 3'-AG splice site (p.Ala1052Phefs*17) (Jeong_2014). The variant was absent in 251096 control chromosomes. c.3154-2A>G has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Laake_2000), individuals undergoing cancer panel testing (Susswein_2016) and at-least one patient with Oesophageal cancer in whom it was grouped among genes known to be associated to a cancer predisposition but as unlikely to have explained the associated cancer phenotype (Bertelsen_2019). These data indicate that the variant may be associated with disease. Five 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000206276	SCV002020742	pathogenic	Ataxia-telangiectasia syndrome	2019-04-08	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000211994	SCV002051705	pathogenic	not provided	2021-01-21	criteria provided, single submitter	clinical testing	PVS1, PM2, PS3_moderate
Institute of Human Genetics, University of Leipzig Medical Center	RCV003128229	SCV003804667	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-01-02	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
Baylor Genetics	RCV003467229	SCV004212009	pathogenic	Familial cancer of breast	2024-02-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467229	SCV004931100	likely pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Natera, Inc.	RCV000206276	SCV001452065	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing