Submissions for variant NM_000051.4(ATM):c.3747-1G>C

dbSNP: rs730881364

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159717	SCV000209729	pathogenic	not provided	2014-06-03	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted ATM c.3747-1G>C or IVS25-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 25 of the ATM gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in the compound heterozygous state with a second ATM variant in a 16 year old male with Fanconi Anemia (Verhagen 2012; note that a typographical error exists in the presentation of this mutation in Table 1 of this publication). Based on the current evidence, we consider ATM c.3747-1G>C to be pathogenic.
Ambry Genetics	RCV000494137	SCV000581477	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The c.3747-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 25 of the ATM gene. This alteration was identified within a cohort of individuals undergoing ATM genetic testing based on a diagnosis of ataxia-telangiectasia (Verhagen MM et al. Hum Mutat, 2012 Mar;33:561-71). This nucleotide position is highly conserved in available vertebrate species. 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). 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215130	SCV001386857	likely pathogenic	Ataxia-telangiectasia syndrome	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 25 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 21665257, 22213089, 26681312). ClinVar contains an entry for this variant (Variation ID: 181950). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000494137	SCV001911457	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.3747-1G>C variant is located in the canonical acceptor splice site of intron 25 and it is predicted to disrupt the canonical acceptor and activate a cryptic acceptor in position c.3760. The use of this new acceptor site would produce a shorter exon 26 and the disruption of the reading frame, triggering nonsense mediated decay (NMD) (PVS1). This variant was found in one ataxia-telangiectasia proband (PS4_Supporting; PMID: 22213089). Splicing analysis in carrier RNA shows the loss of the first 13 nucleotides of exon 26 leading to the predicted frameshift and NDM (A. Osorio, unpublished result). Assays performed with lymphoblastoid cell lines of an ataxia-telangiectasia patient showed that the ATM protein was absent and there was a clearly increased radiosensitivity (PS3_Moderate, PMID: 22213089). The variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PS4_Supporting + PS3_Moderate + PM2 (PMID: 33280026).
Myriad Genetics, Inc.	RCV004019938	SCV004931422	likely pathogenic	Familial cancer of breast	2024-01-22	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.