Submissions for variant NM_000051.4(ATM):c.2639-22_2639-20del

dbSNP: rs1064795554

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002284401	SCV000571480	likely pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing	Non-canonical splice variant demonstrated to result in abnormal splicing (External communication with Ambry Genetics); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 12552559, 26896183)
Color Diagnostics, LLC DBA Color Health	RCV000583624	SCV000687406	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-31	criteria provided, single submitter	clinical testing	This variant causes a 3-nucleotide deletion in the intron 17 splice acceptor site at a predicted branchpoint of the ATM gene. Splicing prediction algorithms have contradictory predictions for the splicing impact. A RNA study has reported that this variant caused abnormal RNA splicing (ClinVar RCV000583624.4). This variant has been reported in two individuals affected with ataxia telangiectasia with the same ATM co-variant c.5177+1G>C (PMID: 26896183) and as a heterozygous mutation in a family affected with ataxia telangiectasia with no other reported pathogenic mutation (PMID: 12552559). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.
Ambry Genetics	RCV000583624	SCV002739690	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	clinical testing	The c.2639-22_2639-20delAAT pathogenic mutation, located in intron 16 of the ATM gene, results from a deletion of 3 nucleotides within intron 16 of the ATM gene. This variant was identified in conjunction with a likely pathogenic variant in ATM in one individual from the UK diagnosed with ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol, 2016 07;58:690-7). These nucleotide positions are well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV003500540	SCV004331490	pathogenic	Ataxia-telangiectasia syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 26896183). ClinVar contains an entry for this variant (Variation ID: 422096). Studies have shown that this variant results in skipping of exon 18 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.