Submissions for variant NM_000051.4(ATM):c.2124+1G>T

dbSNP: rs1555073553

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522113	SCV000621619	likely pathogenic	not provided	2023-04-09	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); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701337	SCV000830134	likely pathogenic	Ataxia-telangiectasia syndrome	2023-08-03	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. Studies have shown that disruption of this splice site results in exon 13 skipping and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 452784). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 32427313). This sequence change affects a donor splice site in intron 13 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	RCV002420323	SCV002726063	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-02-04	criteria provided, single submitter	clinical testing	The c.2124+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 12 of the ATM gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV004023620	SCV004933116	likely pathogenic	Familial cancer of breast	2024-01-17	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.