Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000216788 | SCV000273298 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-01-08 | criteria provided, single submitter | clinical testing | The c.966-1G>A intronic variant, results from a G to A one nucleotide upstream from coding exon 8 of the RAD51C gene. Alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). Based on two different splice site prediction tools, this alteration is expected to abolish the native splice acceptor site; however, a strong alternate acceptor site is predicted only 3 nucleotides upstream of the native site. No experimental splicing evidence is currently available. 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of c.966-1G>A remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780667 | SCV000918126 | uncertain significance | not specified | 2017-11-24 | criteria provided, single submitter | clinical testing | Variant summary: The RAD51C c.966-1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the weakening or complete loss of a cannonical splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 246132 control chromosomes. In addition, one clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is predicted to impact splicing, however it is located close to the end of the protein, therefore the impact of this variant are unclear at this time. It has been classified as a VUS - possibly pathogenic variant. |
| Labcorp Genetics |
RCV003765400 | SCV004624355 | uncertain significance | Fanconi anemia complementation group O | 2023-10-12 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 7 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 229925). Studies have shown that disruption of this splice site results in a frameshift and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. 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. |