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

dbSNP: rs1555073553

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042407	SCV001206085	likely pathogenic	Ataxia-telangiectasia syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 13 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 breast cancer (PMID: 32427313). ClinVar contains an entry for this variant (Variation ID: 840421). 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.
Ambry Genetics	RCV002416352	SCV002726465	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	The c.2124+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 12 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is insufficient at this time (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.	RCV004031286	SCV004931307	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.