Submissions for variant NM_000051.4(ATM):c.5762+1G>A

dbSNP: rs869312756

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572451	SCV000665566	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The c.5762+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 37 of the ATM gene. This variant was identified in 1/317 men in a metastatic prostate cancer cohort undergoing hereditary cancer genetic testing (Boyle JL et al. JCO Precis Oncol, 2020 Mar;4:). 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. 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	RCV000693089	SCV000820944	pathogenic	Ataxia-telangiectasia syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 38 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with prostate cancer (PMID: 32923906). ClinVar contains an entry for this variant (Variation ID: 481271). Studies have shown that disruption of this splice site results in skipping of exon 38, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000572451	SCV002529201	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
GeneDx	RCV002305508	SCV002599758	likely pathogenic	not provided	2022-10-27	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: 32923906)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002305508	SCV004024392	likely pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476328	SCV004212264	likely pathogenic	Familial cancer of breast	2022-05-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003476328	SCV004932434	likely pathogenic	Familial cancer of breast	2024-01-25	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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV005056208	SCV005725446	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2025-02-04	criteria provided, single submitter	clinical testing	PVS1, PM2_SUP, PM5_SUP