Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000411480 | SCV000485862 | likely pathogenic | Ataxia-telangiectasia syndrome | 2016-02-22 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000568118 | SCV000660467 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-29 | criteria provided, single submitter | clinical testing | The c.2377-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 15 in the ATM gene. This alteration was detected in 1/15 patients with Sézary syndrome, a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course (Prasad A et al. J. Invest. Dermatol., 2016 Jul;136:1490-9). It has also been detected in at least one individual from a cohort of 481 Chinese patients with a personal and or family history of breast cancer (Wang J et al. Cancer Med, 2019 05;8:2074-2084). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion deletion of one amino acid(s); however, the exact functional impact of the deleted amino acid is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000568118 | SCV000910309 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-05-18 | criteria provided, single submitter | clinical testing | This variant causes an A to G nucleotide substitution at the -2 position of intron 15 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with Se'zary Syndrome, a leukemic form of cutaneous T-cell lymphoma (PMID: 27039262). 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. |
| Invitae | RCV000411480 | SCV001229353 | likely pathogenic | Ataxia-telangiectasia syndrome | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor 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). Disruption of this splice site has been observed in individual(s) with breast cancer and/or Sézary syndrome (PMID: 27039262, 30982232). ClinVar contains an entry for this variant (Variation ID: 370519). 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. |
| Baylor Genetics | RCV003463794 | SCV004207725 | likely pathogenic | Familial cancer of breast | 2023-08-23 | criteria provided, single submitter | clinical testing |