Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000565146 | SCV000672675 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-09-01 | criteria provided, single submitter | clinical testing | The c.2376+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 14 of the ATM gene. 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. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 180000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted to abolish the native splice donor site and is predicted to weaken (but not abolish) the efficiency of the native splice donor site by BDGP and ESEfinder, respectively; however, direct evidence is unavailable. 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 likely pathogenic. |
| Invitae | RCV002528970 | SCV002930564 | likely pathogenic | Ataxia-telangiectasia syndrome | 2023-11-25 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 15 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). 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: 485204). 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 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. |
| Myriad Genetics, |
RCV004024515 | SCV004932326 | likely pathogenic | Familial cancer of breast | 2024-01-17 | 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. |
| Clinical Genetics Laboratory, |
RCV004696951 | SCV005199605 | likely pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing |