ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1026+5_1026+7del (rs587781410)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116170 SCV000184030 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Color RCV000116170 SCV000691214 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Counsyl RCV000576756 SCV000677795 likely pathogenic Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2016-08-06 criteria provided, single submitter clinical testing
GeneDx RCV000235204 SCV000150079 likely pathogenic not provided 2018-11-15 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.1026+5_1026+7delGTA or IVS8+5_IVS8+7delGTA and consists of a deletion of three nucleotides at the +5 to +7 positions in intron 8 of the RAD51C gene. The normal sequence, with the bases that are deleted in brackets, is gtca[delgta]ttat. This variant has been observed in at least four breast/ovarian cancer families, as well as in one healthy control (Loveday 2012, Golmard 2013, Janatova 2015, Kraus 2017). In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging; however, mRNA studies showed this variant causes out-of-frame skipping of exon 8, resulting in a frameshift and truncated protein (Golmard 2013, Davy 2017). The disrupted region at the end of the gene includes the nuclear localization signal (French 2003). RAD51C c.1026+5_1026+7delGTA was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, we consider RAD51C c.1026+5_1026+7delGTA to be a likely pathogenic variant.
Invitae RCV000197293 SCV000255311 likely pathogenic Fanconi anemia, complementation group O 2018-12-28 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the RAD51C gene. It does not directly change the encoded amino acid sequence of the RAD51C protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587781410, ExAC 0.004%). This variant has been reported in the literature in individuals affected with breast cancer, ovarian cancer, and uterine cancer, as well as in an unaffected control individual (PMID: 22538716, 24139550, 26057125, 27616075, 29255180). Segregation studies have not been reported for this variant. ClinVar also contains an entry for this variant (Variation ID: 128201). This small deletion disrupts the consensus donor splice site at intron 8 of the RAD51C gene. RT-PCR analysis using RNA extracted from the peripheral blood of carrier individuals shows that this variant may lead to the skipping of exon 8, resulting in a frameshift and the generation of a premature stop codon in the final exon of RAD51C (PMID: 24139550, 26057125, 28905878). Although it is not predicted to result in nonsense mediated decay, it does affect the C-terminus of the RAD51C protein, which includes a nuclear localization signal that when deleted has been shown to cause cellular mislocalization (PMID: 12966089). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratoire de Biologie et Génétique du Cancer,Centre François Baclesse RCV000456115 SCV000536678 pathogenic Breast-ovarian cancer, familial 3 criteria provided, single submitter clinical testing
PreventionGenetics RCV000235204 SCV000807165 likely pathogenic not provided 2016-10-17 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000456115 SCV000886446 likely pathogenic Breast-ovarian cancer, familial 3 2018-05-17 criteria provided, single submitter research The RAD51C variant designated as NM_058216.2:c.1026+5_1026+7delGTA was previously classified as a variant of uncertain significance and is now classified as likely pathogenic. This variant is a nucleotide deletion that affects a consensus splice site in intron 8 of the RAD51C gene. RNA studies of peripheral blood from individuals with the variant have demonstrated that the variant leads to skipping of exon 8, resulting in a frameshift and the generation of a premature stop codon in the final exon (Golmard 2013, PMID:241395; Janatova 2015, PMID:26057125). Nonsense-mediated decay is not expected to result from this variant, but it leads to a removal of the nuclear localization signal which can cause cellular mislocalization (French 2003, PMID:12966089). This variant is not listed in population databases. It has been reported in an unaffected control individual and in individuals with breast cancer, ovarian cancer, and uterine cancer in multiple studies (Loveday 2012, PMID:22538716; Golmard 2013, PMID:2413955; Janatova 2015, PMID:26057125; Kraus 2017, PMID:27616075). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 98% probability of pathogenicity based largely on splice prediction and functional studies, which are consistent with a classification of likely pathogenic. This variant is predicted to alter RAD51C function and modify risk for cancer. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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