Submissions for variant NM_000051.4(ATM):c.1898+1G>T

dbSNP: rs758325274

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529407	SCV000622291	pathogenic	Ataxia-telangiectasia syndrome	2023-08-11	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with ataxia-telangiectasia (PMID: 16941484, 17985259). This variant is also known as IVS14 c.1898+1G>T. ClinVar contains an entry for this variant (Variation ID: 453391). Studies have shown that disruption of this splice site results in skipping of skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 16941484). This variant disrupts a region of the ATM protein in which other variant(s) (p.Leu615Pro) have been determined to be pathogenic (PMID: 29368341, 30549301, 32901917; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 12 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Ambry Genetics	RCV000576102	SCV000667968	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-14	criteria provided, single submitter	clinical testing	The c.1898+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 11 of the ATM gene. This mutation has been reported in trans with an ATM multi-exon gross deletion in a patient with ataxia-telangiectasia (AT) and was shown to cause exon-skipping (Cavalieri S et al. Hum. Mutat. 2006 Oct;27:1061). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, 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 pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000576102	SCV001343919	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 12 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been reported in the compound heterozygous state in an individual affected with ataxia-telangiectasia (PMID: 16941484). RNA analysis of lymphoblastoid cell lines derived from this person reportedly showed skipping of exon 12 (PMID: 16941484). 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.
Myriad Genetics, Inc.	RCV004023633	SCV004931591	likely pathogenic	Familial cancer of breast	2024-01-16	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.
Natera, Inc.	RCV000529407	SCV001461016	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing