Submissions for variant NM_000051.4(ATM):c.902-1G>T

gnomAD frequency: 0.00001  dbSNP: rs1064793518

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478968	SCV000566311	pathogenic	not provided	2022-11-11	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: 29922827, 23807571, 23585524, 26247737, 27304073, 25614872, 35716007, 29101607, 10330348, 34262154)
Ambry Genetics	RCV000493667	SCV000581462	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	The c.902-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 7 of the ATM gene. This mutation was detected in a compound heterozygous state with a second ATM mutation in an individual with ataxia telangiectasia (AT). On cDNA synthesized from patient mRNA, authors observed transcripts lacking coding exon 7, which is predicted to result in a frameshift and alternate stop codon (Teraoka SN et al, Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31). This alteration was also seen in one individual with a family history of pancreatic cancer (Barnes CA et al. Fam. Cancer, 2018 01;17:101-111). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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	RCV000685477	SCV000812959	pathogenic	Ataxia-telangiectasia syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 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 (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia in whom it co-occurs with a second pathogenic ATM variant (PMID: 10330348). This variant is also known as IVS9-1G>T. ClinVar contains an entry for this variant (Variation ID: 418911). Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 10330348; 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	RCV000493667	SCV000911165	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-06	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 7 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study using carrier-derived RNA has shown that this variant causes the skipping of exon 8, creating a premature translation stop signal in the RNA transcript (PMID: 10330348). The aberrant transcript is expected to result in an absent or non-functional protein product. This variant (also known as IVS9-1G>T in the literature) has been reported in trans with an additional pathogenic ATM variant in an individual affected with ataxia telangiectasia (PMID: 10330348). This variant has also been reported in an individual with family history of pancreatic cancer (PMID: 29101607). This variant has been identified in 1/250328 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.
MGZ Medical Genetics Center	RCV002289623	SCV002580857	pathogenic	Familial cancer of breast	2022-06-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000478968	SCV004010112	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ATM: PVS1, PM2
Institute of Human Genetics, University of Leipzig Medical Center	RCV002289623	SCV004027780	pathogenic	Familial cancer of breast	2023-12-28	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3_MOD,PS4_MOD,PM2_SUP
Baylor Genetics	RCV002289623	SCV004212156	pathogenic	Familial cancer of breast	2022-12-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289623	SCV004931542	pathogenic	Familial cancer of breast	2024-01-11	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. Functional studies indicate this variant impacts protein function [PMID: 10330348].
Natera, Inc.	RCV000685477	SCV001456869	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing