Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000570679 | SCV000667804 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-10-28 | criteria provided, single submitter | clinical testing | The c.8418+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 56 in the ATM gene. 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). Another alteration impacting the same donor site, c.8418+5_8418+8delGTGA, has been shown to have a similar impact on splicing and has been reported in multiple individuals with a clinical diagnosis of ataxia-telangiectasia (A-T) (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59(4):839-46; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62(2):334-45; Li A and Swift M. Am. J. Med. Genet. 2000 May;92(3):170-7; Buzin CH et al. Hum. Mutat. 2003 Feb;21(2):123-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV000628150 | SCV000749043 | uncertain significance | Ataxia-telangiectasia syndrome | 2022-12-21 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 57 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 present in population databases (no rsID available, gnomAD 0.0009%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 482524). This variant has not been reported in the literature in individuals affected with ATM-related conditions. |
| Sema4, |
RCV000570679 | SCV002527285 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-16 | criteria provided, single submitter | curation |