Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000166211 | SCV000216990 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-10-19 | criteria provided, single submitter | clinical testing | The c.901+3A>T intronic variant results from an A to T substitution 3 nucleotides after coding exon 6 in the ATM gene. This alteration was detected in a single Swedish family affected with Ataxia Telagiectasia and was categorized as most likely disease causing due to predicted exon skipping (Laake K et al Hum Mutat. 2000 Sep;16(3):232-46). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 22,000 alleles tested) in our clinical cohort. This nucleotide position is well conserved in available vertebrate species. In addition, this alteration is predicted to abolish the native donor site by the BDGP in silico model and significantly weaken the native donor site by the ESEfinder in silico model; however experimental evidence is not currently available. Since supporting evidence is limited at this time, the clinical significance of c.901+3A>T remains unclear. |
Color Diagnostics, |
RCV000166211 | SCV000913536 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-11-19 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV003500509 | SCV004296141 | likely pathogenic | Ataxia-telangiectasia syndrome | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 7 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 ataxia-telangiectasia (PMID: 10980530). This variant is also known as IVS9+3 A>T. ClinVar contains an entry for this variant (Variation ID: 186593). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. |