ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.837+1G>T

dbSNP: rs760235677
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
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
GeneDx 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, Inc. 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, LabCorp 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.