Submissions for variant NM_000051.4(ATM):c.4110-1G>A

dbSNP: rs1060501692

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462992	SCV000547109	pathogenic	Ataxia-telangiectasia syndrome	2023-04-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in altered splicing and introduces a premature termination codon (PMID: 14695534). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 14695534). ClinVar contains an entry for this variant (Variation ID: 407707). This variant is also known as IVS29-1G>A. Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 14695534). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 27 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.
Ambry Genetics	RCV000566126	SCV000667952	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	clinical testing	The c.4110-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 27 of the ATM gene. This alteration (designated as IVS29-1G>A) was previously detected in a Hispanic individual diagnosed with ataxia-telangiectasia and was shown to disrupt the native acceptor splice site, resulting in a new splice site and deletion of the first nucleotide of the next coding exon which leads to a frameshift (Eng L et al. Hum Mutat. 2004 Jan;23:67-76). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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.
Color Diagnostics, LLC DBA Color Health	RCV000566126	SCV001341159	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -1 position of intron 27 of the ATM gene. Functional RNA studies have shown that this variant (described as IVS29-1G>A) disrupts a canonical splice site and activates a cryptic splice site one nucleotide downstream, resulting in a frameshift and premature stop codon (PMID: 14695534). This variant has been reported in an individual affected with ataxia telangiectasia (PMID: 14695534). 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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310115	SCV001499657	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000566126	SCV002528996	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	curation
Baylor Genetics	RCV001310115	SCV004212151	pathogenic	Familial cancer of breast	2022-12-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001310115	SCV004931319	likely pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing	This variant is considered likely 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.