ClinVar Miner

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

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Total submissions: 14
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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 2018-09-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study;Other data supporting benign classification
Invitae RCV000233123 SCV000287731 likely benign Breast-ovarian cancer, familial 4 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000233123 SCV000488842 uncertain significance Breast-ovarian cancer, familial 4 2016-07-18 criteria provided, single submitter clinical testing
Color Health, Inc 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000679543 SCV001747873 likely benign not provided 2021-05-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000233123 SCV001934383 uncertain significance Breast-ovarian cancer, familial 4 2021-01-05 criteria provided, single submitter clinical testing
King Laboratory,University of Washington RCV000212974 SCV001251346 benign not specified 2019-09-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354829 SCV001549539 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The RAD51D c.904-3C>T variant was identified in 3 of 9008 proband chromosomes (frequency: 0.0003) from individuals or families with colorectal, breast and ovarian cancer and was present in 1 of 2120 control chromosomes (frequency: 0.004) from healthy individuals (Yurgelun 2015, Osher 2012, Tung 2015, Loveday 2011). The variant was identified in dbSNP (rs45478491) as “with uncertain significance allele” and ClinVar (classified as likely benign by Ambry Genetics, Color and 2 other submitters and uncertain significance by Invitae, Counsyl and 1 other submitter and benign by GeneDx). The variant was identified in control databases in 63 of 277,232 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,038 chromosomes (freq: 0.0002), Other in 2 of 6468 chromosomes (freq: 0.0003), Latino in 7 of 34,420 chromosomes (freq: 0.0002), European in 50 of 126,710 chromosomes (freq: 0.0004), but was not observed in the Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The c.904-3C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. The variant occurs at a non-conserved nucleotide and 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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