Submissions for variant NM_000051.4(ATM):c.497-1G>T

dbSNP: rs778624615

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000988640	SCV001138431	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001805955	SCV002051873	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 5 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988640	SCV002250101	likely pathogenic	Ataxia-telangiectasia syndrome	2022-05-20	criteria provided, single submitter	clinical testing	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 activation of a cryptic splice site 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: 802723). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 5 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	RCV001805955	SCV002644283	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-31	criteria provided, single submitter	clinical testing	The c.497-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 5 of the ATM gene. 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; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Baylor Genetics	RCV003467549	SCV004212045	likely pathogenic	Familial cancer of breast	2023-03-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467549	SCV004932331	likely pathogenic	Familial cancer of breast	2024-01-09	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.