ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2376+1G>A

dbSNP: rs730881347
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000583695 SCV000687380 likely pathogenic Hereditary cancer-predisposing syndrome 2023-02-15 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 15 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have shown this variant disrupts splicing and results in in-frame skipping of exon 15 (PMID: 35716007). This variant has been reported in the compound heterozygous state in an individual affected with ataxia-telangiectasia (PMID: 22213089, 28126470). In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 unaffected controls (PMID: 33471991). 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 RCV001224699 SCV001396914 likely pathogenic Ataxia-telangiectasia syndrome 2019-09-18 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. Donor and acceptor splice site variants 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 has been observed in combination with another ATM variant in an individual affected with ataxia-telangiectasia (A-T) (PMID: 22213089). ClinVar contains an entry for this variant (Variation ID: 490469). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 15 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Baylor Genetics RCV003465298 SCV004212252 pathogenic Familial cancer of breast 2022-06-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000583695 SCV005168347 likely pathogenic Hereditary cancer-predisposing syndrome 2024-04-09 criteria provided, single submitter clinical testing The c.2376+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the ATM gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been identified in conjunction with another ATM variant in an individual diagnosed with ataxia telangiectasia; however, the phase of the two variants was not specified (Verhagen MM et al. Hum Mutat, 2012 Mar;33:561-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001726253 SCV001963599 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001726253 SCV001965802 likely pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.