Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000220072 | SCV000273820 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-02-17 | criteria provided, single submitter | clinical testing | The c.496+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 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 0.002% (greater than 41,000 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 by ESEfinder to abolish the native donor splice site, and is predicted to weaken (but not abolish) the efficacy of the native donor splice site by BDGP; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.496+1G>A remains unclear. |
Labcorp Genetics |
RCV001379244 | SCV001577005 | likely pathogenic | Ataxia-telangiectasia syndrome | 2020-09-09 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 5 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 230315). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). 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. |