Submissions for variant NM_000051.4(ATM):c.5675-7_5675-4del

dbSNP: rs1189695629

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537967	SCV000622616	pathogenic	Ataxia-telangiectasia syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change falls in intron 37 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 453597). Studies have shown that this variant results in exon 38 skipping 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.
Color Diagnostics, LLC DBA Color Health	RCV001178546	SCV001343010	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-30	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides of intron 37 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001584235	SCV001810784	likely pathogenic	not provided	2024-04-15	criteria provided, single submitter	clinical testing	RNA studies demonstrate aberrant splicing (External communication with Invitae and Ambry Genetics); Observed in an individual with ataxia-telangiectasia who also harbored a second ATM variant; however, it is unknown whether the variants are on the same or opposite chromosomes (in cis or trans) (PMID: 34477998); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34477998)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001584235	SCV002010803	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001178546	SCV002647805	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-08	criteria provided, single submitter	clinical testing	The c.5675-7_5675-4delTTGT intronic variant, located in intron 36 of the ATM gene, results from a deletion of 4 nucleotides within intron 36 of the ATM gene. This nucleotide region is well 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323589	SCV004028596	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5675-7_5675-4delTTGT deleted conserved nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' splice acceptor site, and one predicts the variant weakens this site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250386 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5675-7_5675-4delTTGT has been reported in the literature in an individual affected with Ataxia-Telangiectasia without IgA deficiency or cancer (Zielen_2021), and they were reported as compound heterozygous with a likely pathogenic variant. These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34477998). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Athena Diagnostics	RCV001584235	SCV004229257	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools yielded inconclusive predictions regarding the effect of this variant on RNA splicing.
Natera, Inc.	RCV000537967	SCV002077193	uncertain significance	Ataxia-telangiectasia syndrome	2020-10-23	no assertion criteria provided	clinical testing