Submissions for variant NM_000051.4(ATM):c.3994-1G>T

dbSNP: rs1057516238

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411542	SCV000485338	likely pathogenic	Ataxia-telangiectasia syndrome	2015-11-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562309	SCV000667937	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	The c.3994-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 26 of the ATM gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000562309	SCV000687512	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-10-11	criteria provided, single submitter	clinical testing	This variant causes a G>T nucleotide substitution at the -1 position of intron 26 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. 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. Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411542	SCV000947547	pathogenic	Ataxia-telangiectasia syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 26 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with pancreatic cancer (PMID: 35047863). ClinVar contains an entry for this variant (Variation ID: 370107). Studies have shown that disruption of this splice site results in skipping of exon 27 or activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003470322	SCV004212206	likely pathogenic	Familial cancer of breast	2022-09-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003470322	SCV004932226	likely pathogenic	Familial cancer of breast	2024-01-23	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.