ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.904-3C>T (rs45478491)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212974 SCV000171279 benign not specified 2014-02-26 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000130350 SCV000185201 likely benign Hereditary cancer-predisposing syndrome 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),No disease association in small case-control study,Other data supporting benign classification
Invitae RCV000233123 SCV000287731 uncertain significance Breast-ovarian cancer, familial 4 2018-12-28 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the RAD51D gene. It does not directly change the encoded amino acid sequence of the RAD51D protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs45478491, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 138877). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
Counsyl RCV000233123 SCV000488842 uncertain significance Breast-ovarian cancer, familial 4 2016-07-18 criteria provided, single submitter clinical testing
Color RCV000130350 SCV000691378 likely benign Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679543 SCV000806591 likely benign not provided 2017-12-06 criteria provided, single submitter clinical testing
Mendelics RCV000709429 SCV000839171 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212974 SCV000918141 likely benign not specified 2018-10-29 criteria provided, single submitter clinical testing Variant summary: RAD51D c.904-3C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 279352 control chromosomes, predominantly at a frequency of 0.00039 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.904-3C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and Lynch Syndrome (Yurgelun_2015, Osher_2012, Tung_2015), however it was also observed in controls (Loveday_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign x3 and VUS x3). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679543 SCV001134808 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing
Mendelics RCV000233123 SCV001140405 uncertain significance Breast-ovarian cancer, familial 4 2019-05-28 criteria provided, single submitter clinical testing

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.