Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000167267 | SCV000218108 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2014-12-16 | criteria provided, single submitter | clinical testing | The c.3164+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 20 of the RAD50 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 6500 samples (13000 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 40,000 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.3164+1G>A variant is classified as likely pathogenic. |
| Invitae | RCV000167267 | SCV002112322 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-15 | criteria provided, single submitter | clinical testing | 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. 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: 187532). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 20 of the RAD50 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 RAD50 are known to be pathogenic (PMID: 19409520). |