Submissions for variant NM_000051.4(ATM):c.2466+5G>C

dbSNP: rs1064795969

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486136	SCV000572290	uncertain significance	not provided	2022-03-30	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); Observed in a patient with ataxia telangiectasia with a second variant but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Villagaray-Pacheco et al., 2021)
Color Diagnostics, LLC DBA Color Health	RCV000580666	SCV000682057	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +5 position of intron 16 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 to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV001176476.3). This variant has been reported in trans with a variant of uncertain significance in an individual affected with ataxia-telangiectasia (DOI:10.37897/RJN.2021.2.11). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800097	SCV000939797	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 16 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). 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: 422744). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000580666	SCV001176476	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The c.2466+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 15 in the ATM gene. This alteration was reported in an individual diagnosed with ataxia telangiectasia (A-T) (Villagaray-Pacheco et al. Ro J Neurol, 2021;20-2). In addition, another alteration impacting the same donor site (c.2466+1delG) has been detected in trans with a second ATM alteration in an individual diagnosed with A-T (Cavalieri S et al. Ann Hum Genet, 2008 Jan;72:10-8). 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. 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.