Submissions for variant NM_000051.4(ATM):c.3993+1G>A

gnomAD frequency: 0.00001  dbSNP: rs200196781

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129961	SCV000184785	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The c.3993+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 25 of the ATM gene. This alteration has been described in several ataxia-telangiectasia families (Laake K et al. Hum. Mutat. 2000; 16:232-46; Mitui M et al. Hum. Mutat. 2003; 22:43-50). This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This alteration has also been identified in patients with pancreatic cancer (Young EL et al. BMC Cancer, 2018 Jun;18:697). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Of note, this alteration is also designated as IVS28+1G>A in published literature. 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 pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228950	SCV000282950	pathogenic	Ataxia-telangiectasia syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 26 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 40 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs200196781, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 10980530, 12815592). 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 IVS28+1G>A. ClinVar contains an entry for this variant (Variation ID: 141447). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 26 (PMID: 10980530; internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000438634	SCV000515987	pathogenic	not provided	2022-08-05	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15390180, 15039971, 29945567, 10980530, 26976419, 25186627, 32853339, 12815592)
Counsyl	RCV000228950	SCV000678090	pathogenic	Ataxia-telangiectasia syndrome	2017-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129961	SCV000687508	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 26 of the ATM gene. A study using carrier-derived RNA has shown that this variant (also known as IVS28+1G>A in the literature) causes the deletion of 120 nucleotides from the 3' end of exon 26 (PMID: 10980530). The aberrant transcript is predicted to cause an in-frame deletion of 40 amino acids (p.Val1292_Gln1331del). This variant has been reported in trans with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 10980530, 12815592). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 26976419) and pancreatic cancer (PMID: 29945567). In a large international case-control study, this variant was reported in 4/60462 breast cancer cases and 5/53456 controls (OR=0.707, 95%CI 0.19 to 2.634, p-value=0.743; PMID: 33471991). This variant has been identified in 4/250838 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 Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000228950	SCV002767913	pathogenic	Ataxia-telangiectasia syndrome	2021-05-06	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). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Using RNA studies, this variant has been reported to result in an in-frame deletion of 40 amino acids (PMID: 10980530). However, specific data was not shown. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and pathogenic in multiple submissions in ClinVar. It has also been reported as compound heterozygous in a patient with ataxia-telangiectasia (PMID: 12815592). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000438634	SCV004027217	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003155921	SCV004212088	pathogenic	Familial cancer of breast	2023-02-16	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000438634	SCV005199608	pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV005055598	SCV005725453	likely pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2025-02-04	criteria provided, single submitter	clinical testing	PVS1;_Strong; PM3_Strong
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005055598	SCV006056791	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-12-05	criteria provided, single submitter	clinical testing
BRCAlab, Lund University	RCV003155921	SCV002588844	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing