Submissions for variant NM_000051.4(ATM):c.2921+1G>A

dbSNP: rs587781558

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129576	SCV000184358	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-08	criteria provided, single submitter	clinical testing	The c.2921+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 18 of the ATM gene. This mutation is also designated as IVS21+1G>A and 2839del83 in published literature. This mutation has previously been reported in the literature in clinically affected individuals with ataxia-telangiectasia in both compound heterozygous and homozygous forms (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Castellvi-Bel S et al. Hum. Mutat. 1999;14:156-62; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94). The c.2921+1G>A mutation has also been shown to lead to exon skipping resulting in a frameshift and premature protein truncation (García-Pérez MA et al. Clin. Exp. Immunol. 2001 Mar;123:472-80). RNA studies have demonstrated that this alteration results in the same splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000169059	SCV000220222	likely pathogenic	Ataxia-telangiectasia syndrome	2014-04-03	criteria provided, single submitter	literature only
GeneDx	RCV000215085	SCV000278817	pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Garcia-Perez et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS21+1G>A; This variant is associated with the following publications: (PMID: 11382771, 29486991, 28888541, 25525159, 12815592, 10425038, 11298136, 23322442, 10330348, 21445571, 21665257, 12673797, 12552559, 24663073, 27443514, 28152038, 8845835, 26689913, 32832836, 31589614, 32427313, 33280026, 32853339, 33462019, 32782288, 29625052, 29922827, 31214711, 31741144, 31050087, 1300551, 8968760, 34204722, 25614872)
Color Diagnostics, LLC DBA Color Health	RCV000129576	SCV000537641	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 19 of the ATM gene. An RNA study has shown that this variant causes the skipping of exon 19 (also known as exon 21 in the literature), creating a premature translation stop signal in the RNA transcript (PMID: 11298136). The aberrant transcript is expected to result in an absent or non-functional protein product. This variant is also known as IVS21+1G>A and 2839del83 in the literature. This variant has been observed in individuals affected with familial breast cancer (PMID: 33462019, 34204722) and prostate cancer (PMID: 31214711, 32315455, 35652560). This variant has also been reported in homozygous and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 8845835, 11298136, 12673797, 12815592, 23322442, 34337741). This variant has been identified in 6/251304 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169059	SCV000546716	pathogenic	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 19 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 present in population databases (rs587781558, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835, 11298136, 12673797, 12815592, 23322442). 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: 141182). Studies have shown that disruption of this splice site results in skipping of exon 19 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507017	SCV000602557	pathogenic	not specified	2016-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169059	SCV000694238	pathogenic	Ataxia-telangiectasia syndrome	2017-01-19	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.2921+1G>A variant involves the alteration of a conserved intronic nucleotide, which 4/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts the removal of an ESE binding site. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121072 (1/40355), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasia. Multiple publications cite the variant in A-T patients that were homozygous or compound heterozygous. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762820	SCV000893178	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-03-23	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000129576	SCV001911455	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.2921+1G>A variant is located in the canonical donor splice site of intron 19, and it is predicted to cause the skipping of exon 19 and disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.000021 (0.002%, 5/236,780 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.000067 (0.006721%, 1/14878 alleles) in the African subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been described in trans with a (likely) pathogenic ATM variant in three ataxia-telangiectasia probands and in homozygosis in two additional ataxia-telangiectasia probands, which awards 4 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong ; PMID: 8968760; PMID: 11298136; PMID: 12815592). Moreover, there is an RNA assay which confirms the deletion of 83bp of exon 19 leading to NMD (PS3_Supporting; PMID: 11298136). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_VeryStrong + PS3_Supporting (PMID: 33280026).
Revvity Omics, Revvity	RCV000169059	SCV002022433	pathogenic	Ataxia-telangiectasia syndrome	2019-02-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000215085	SCV002064366	pathogenic	not provided	2019-12-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change in the canonical splice donor site of intron 19, c.2921+1G>A. This sequence change has been previously described in patients with Ataxia-telangiectasia in both homozygous and compound heterozygous state (Garc?a-P?rez et al., 2001; Gilad et al., 1996 and Jeddane et al., 2013). This sequence change has been described in the gnomAD database with a population frequency of 0.0024% (rs587781558). This sequence change is predicted to affect normal splicing of the ATM gene and result in an abnormal protein. These collective evidences indicate that this sequence change is pathogenic. This sequence change was identified with another likely pathogenic ATM variant in a patient.
Sema4, Sema4	RCV000129576	SCV002532963	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000169059	SCV003807322	pathogenic	Ataxia-telangiectasia syndrome	2022-08-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 strong
CeGaT Center for Human Genetics Tuebingen	RCV000215085	SCV004010113	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	ATM: PVS1, PM3:Strong, PM2, PS3:Supporting
Illumina Laboratory Services, Illumina	RCV000169059	SCV004014649	pathogenic	Ataxia-telangiectasia syndrome	2023-03-14	criteria provided, single submitter	clinical testing	The ATM c.2921+1G>A variant results in the substitution of a guanine within the consensus splice donor site with an adenine which has been shown to result in splicing defects (PMID: 11298136). This variant has been reported in at least three individuals with ataxia-telangiectasia including in two individuals in a homozygous state and in one individual in a compound heterozygous state (PMID: 8845835; PMID: 12673797). This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000123 in the African/African American population. The c.2921+1G>A variant was identified in trans with a second ATM variant. Based on the available evidence, the c.2921+1G>A variant is classified as pathogenic for ataxia-telangiectasia.
Baylor Genetics	RCV003467112	SCV004206936	pathogenic	Familial cancer of breast	2024-03-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000215085	SCV004220893	pathogenic	not provided	2014-04-29	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal ATM mRNA splicing. The frequency of this variant in the general population, 0.00012 (2/16230 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with breast cancer (PMIDs: 12673797 (2003), 21445571 (2011)), and with ataxia-telangiectasia (PMIDs: 8845835 (1996), 12673797 (2003), 12815592 (2003), 23322442 (2013), 30338439 (2019)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003467112	SCV004931087	pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This variant is considered 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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8845835, 10425038, 12815592, 23322442, 31741144].
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003467112	SCV005398893	pathogenic	Familial cancer of breast	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900) and susceptibility to breast cancer (MIM#114480). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic variants in this gene result in ataxia-telangiectasia; however, heterozygous carriers of specific pathogenic variants have an increased risk of breast cancer (PMID: 27595995). Germline variants in this gene may also contribute to increased risk of other cancers including gastric, colorectal, and pancreatic cancers, however the risk is not well-established at this stage (PMIDs: 22585167, 27978560, 26506520). (I) 0115 - Variants in this gene are known to have variable expressivity with regard to ataxia-telangiectasia. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. cDNA analysis demonstrates that this variant causes exon skipping, the deletion of 83 nucleotides results in a stop gain downstream that is predicted to undergo nonsense-mediated decay (PMID: 11298136). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (16 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (6 heterozygotes, 0 homozygotes). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). In addition, other changes at the same canonical splice region (c.2921+1G>C, c.2921+1G>T and c.2921+2T>G) have also been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic in compound heterozygotes and homozygotes with ataxia-telangiecstasia (MIM#208900) and in heterozygous breast cancer patients (ClinVar, PMID: 34204722). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Franklin by Genoox	RCV000215085	SCV000916301	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169059	SCV001452057	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128149	SCV003804340	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739431	SCV005359032	pathogenic	ATM-related disorder	2024-05-23	no assertion criteria provided	clinical testing	The ATM c.2921+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported to be causative for autosomal recessive ataxia telangiectasia (A-T) (HGMD: Gilad et al. 1996. PubMed ID: 8845835, reported as 2839del83; García-Pérez et al. 2001. PubMed ID: 11298136, reported as IVS21+1G>CA). Studies have shown that heterozygous female relatives of A-T patients have an increased risk of developing breast cancer when compared to the general population (Swift et al. 1976. PubMed ID: 1248000; Renwick et al. 2006. PubMed ID: 16832357). The c.2921+1G>A variant was identified in a screening study of Spanish patients with hereditary breast cancer (Grana et al. 2011. PubMed ID: 21445571). Additionally, the c.2921+1G>A variant has also been reported in a patient with colorectal cancer (Supp. Table 9, AlDubayan et al. 2018. PubMed ID: 29478780), in a male with breast cancer (Supplementary Table 2, Tung et al. 2015. PubMed ID: 25186627), and a sequenced mesothelioma tumor of unknown subtype (Supp. Table 2, Kato et al. 2016. PubMed ID: 27507853). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141182/). Variants that disrupt the consensus splice donor site in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.