Submissions for variant NM_000051.4(ATM):c.332-1G>A

gnomAD frequency: 0.00001  dbSNP: rs747855862

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221517	SCV002499301	pathogenic	Familial cancer of breast	2022-11-22	reviewed by expert panel	curation	The ATM c.332-1G>A variant is predicted to create an NMD-escaping transcript resulting in a loss of part of the HEAT repeat domain (PVS1_strong). This variant has been observed in a compound heterozygous state (confirmed) in one individual with Ataxia-Telangiectasia (PMID: 10980530, PM3_strong). This variant is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel.
Ambry Genetics	RCV000217634	SCV000275414	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	criteria provided, single submitter	clinical testing	The c.332-1G>A pathogenic intronic variant results from a G to A substitution one nucleotide upstream from coding exon 4 of the ATM gene. This alteration has been detected in an individual with ataxia-telangiectasia confirmed in trans with another ATM pathogenic mutation, and RNA analysis of this alteration showed skipping of exon 5 leading to an in-frame deletion of 165 base pairs or 55 amino acids (Laake K et al. Hum. Mutat. 2000 Sep; 16(3):232-46). Another study detected this alteration in 0/3030 patients with pancreatic cancer, 1/53105 controls from the ExAC population database, and 0/123136 controls from the gnomAD population database (Hu C et al. JAMA. 2018 06;319:2401-2409). In silico splice site analysis predicts that this alteration will weaken the native 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000480467	SCV000567228	likely pathogenic	not provided	2018-03-28	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted ATM c.332-1G>A or IVS4-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 4 of the ATM gene. A splicing assay reportedly demonstrated that this variant, also defined as IVS6-1G>A using alternate numbering, results in the skipping of the adjacent exon (Laake 2000). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. ATM c.332-1G>A was observed in trans with another ATM variant in an individual with Ataxia-Telangiectasia (Laake 2000). Based on currently available evidence, we consider this variant to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519688	SCV003293312	likely pathogenic	Ataxia-telangiectasia syndrome	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs747855862, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 10980530). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS6-1 G>A. ClinVar contains an entry for this variant (Variation ID: 231535). Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 10980530; internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000480467	SCV004243400	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002221517	SCV004932053	pathogenic	Familial cancer of breast	2024-01-09	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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].
BRCAlab, Lund University	RCV002221517	SCV002588910	likely pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing