Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000226369 | SCV000291249 | pathogenic | Fanconi anemia complementation group O | 2023-06-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 21616938; Invitae). ClinVar contains an entry for this variant (Variation ID: 241779). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28802053, 32107557). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the RAD51C 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 RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). |
Counsyl | RCV000226369 | SCV000489917 | likely pathogenic | Fanconi anemia complementation group O | 2016-08-10 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000409098 | SCV000489918 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 3 | 2016-08-10 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000481912 | SCV000570749 | likely pathogenic | not provided | 2023-08-25 | criteria provided, single submitter | clinical testing | Canonical splice site variant demonstrated to cause abnormal splicing, resulting in an in-frame loss of the adjacent exon in the majority of transcripts, in a gene for which loss of function is a known mechanism of disease (Sanoguera-Miralles et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individual(s) with ovarian cancer (Lu et al., 2019); This variant is associated with the following publications: (PMID: 21616938, 27908594, 28802053, 32107557, 14704354, 30128536, 35740625) |
Ambry Genetics | RCV003298308 | SCV004000892 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-13 | criteria provided, single submitter | clinical testing | The c.837+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 5 of the RAD51C gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Drexler GA et al. DNA Repair (Amst.) 2004 Oct;3(10):1335-43)). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Myriad Genetics, |
RCV000409098 | SCV004019972 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 3 | 2023-04-05 | 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317171 | SCV004021269 | pathogenic | Hereditary breast ovarian cancer syndrome | 2023-06-12 | criteria provided, single submitter | clinical testing | Variant summary: RAD51C c.837+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Experimental evidence support these predictions demonstrating that this variant affects mRNA splicing, leading to in-frame skipping of exon 5 (Sanoguera-Miralles_2022). The variant was absent in 251374 control chromosomes (gnomAD). c.837+1G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Swisher_2017, Lu_2019). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30128536, 35740625, 27908594). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |