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

dbSNP: rs587781558

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130866	SCV000185765	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	The c.2921+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 18 of the ATM gene. Another alteration at this same nucleotide position has been reported in a homozygous state in one patient with a clinical diagnosis of ataxia-telangiectasia and in a compound heterozygous state in three patients with clinical diagnoses of ataxia-telangiectasia (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Castellví-Bel S et al. Hum. Mutat. 1999;14:156-62; García-Pérez MA et al. Clin. Exp. Immunol. 2001 Mar;123:472-80; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50). In addition to the clinical data presented in the literature, RNA studies detected abnormal splicing in individuals with the c.2921+1G>T alteration (Ambry internal data). As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233536	SCV000282914	pathogenic	Ataxia-telangiectasia syndrome	2023-12-17	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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with ataxia-telangiectasia, colorectal cancer (PMID: 8845835, 11298136, 29478780). ClinVar contains an entry for this variant (Variation ID: 142057). Studies have shown that disruption of this splice site results in skipping of exon 19 and introduces a premature termination codon (PMID: 11298136; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130866	SCV000687426	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 19 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. A different variant affecting the same nucleotide position (c.2921+1G>A) is considered to be disease-causing (ClinVar variation ID: 141182), suggesting that the reference nucleotide at this position is important for normal RNA splicing. This variant has been reported in individuals affected with breast cancer (PMID: 34204722) or colorectal cancer (PMID: 29478780). 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 Likely Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000233536	SCV000746373	pathogenic	Ataxia-telangiectasia syndrome	2017-12-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001571421	SCV001795895	pathogenic	not provided	2020-01-24	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29478780, 28152038)
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000130866	SCV001911456	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.2921+1G>T 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 is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). There is a pathogenic variant (c.2921+1G>A) in the same position, and the in silico splicing algorithm SPiCE predicts the same impact for both variants (PS1_Supporting). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS1_Supporting (PMID: 33280026).
Sema4, Sema4	RCV000130866	SCV002532974	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330505	SCV004037703	likely pathogenic	Malignant tumor of breast	2023-08-01	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2921+1G>T 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: Three predict the variant abolishes the canonical 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251304 control chromosomes. c.2921+1G>T has been reported in the literature in two individuals affected with Colorectal cancer and early onset Rhabdomyosarcoma, respectively (examples: AlDubayan_2018, Kim_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different change c.2921+1G>A at this location has been reported in individuals with breast cancer and ovarian cancer and with ataxia-telangiectasia (Pathogenic at Labcorp with Ataxia Telangiectasia, 17 Pathogenic/clinical testing in ClinVar). The following publications have been ascertained in the context of this evaluation (PMID: 29478780, 34308104). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003462003	SCV004213971	likely pathogenic	Familial cancer of breast	2021-10-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003462003	SCV004932944	pathogenic	Familial cancer of breast	2024-01-22	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.
Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences	RCV000233536	SCV003936077	pathogenic	Ataxia-telangiectasia syndrome		no assertion criteria provided	research