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

dbSNP: rs587781410

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235204	SCV000150079	likely pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and published functional studies demonstrate a damaging effect on splicing (Golmard et al., 2013; Kraus et al., 2017; Sanoguera-Miralles et al., 2020); Observed in individuals with a personal or family history of breast and/or ovarian cancer (Loveday et al., 2012; Golmard et al., 2013; Janatova et al, 2015; Kraus et al., 2017; Penkert et al., 2018; Tsai et al., 2019; Jarhelle et al., 2019; Fanale et al., 2020; Germani et al., 2020; Boni et al., 2021; Bono et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24139550, 27616075, 22538716, 26057125, 25470109, 27621404, 12966089, 28905878, 26681312, 33753322, 32957588, 32854451, 31589614, 30374176, 29978187, 35740625, 34371384, 31882575, 30086788, 34923718, 34887416, 30257646, 28888541, 29922827, 33333735)
Ambry Genetics	RCV000116170	SCV000184030	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing	The c.1026+5_1026+7delGTA intronic variant results from a deletion of 3 nucleotides from the +5 to +7 positions after coding exon 8 in the RAD51C gene. This alteration has been identified in high-risk breast and ovarian cancer families (Loveday C et al. Nat. Genet. 2012 May;44:475-6; Golmard L et al. BMC Cancer. 2013 Oct;13:484; Janatova M et al. PLoS One. 2015 Jun;10:e0127711; Susswein LR et al. Genet Med, 2016 08;18:823-32; Golmard L et al. Eur J Hum Genet, 2017 12;25:1345-1353; Penkert J et al. Breast Cancer Res, 2018 08;20:87; Hoyer J et al. BMC Cancer, 2018 Sep;18:926; Jarhelle E et al. Sci Rep, 2019 12;9:19986; Fanale D et al. Cancers (Basel), 2020 Aug;12). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and multiple studies have demonstrated exon 8 skipping associated with this allele (Golmard L et al. BMC Cancer. 2013 Oct;13:484; Janatova M et al. PLoS One. 2015 Jun;10:e0127711; Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec; Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12; Ambry internal data). The deleted region is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000197293	SCV000255311	likely pathogenic	Fanconi anemia complementation group O	2024-01-29	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. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs747311993, gnomAD 0.003%). This variant has been observed in individual(s) with breast cancer, ovarian cancer, kidney cancer, and uterine cancer (PMID: 22538716, 24139550, 26057125, 27616075, 29255180, 29978187, 30086788, 30257646, 30374176, 31882575). ClinVar contains an entry for this variant (Variation ID: 128201). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 8 skipping and introduces a new termination codon (PMID: 24139550, 26057125, 28905878, 31843900; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts the C-terminus of the RAD51C protein, which contains a signal required for nuclear localization (PMID:12966089). While functional studies have not been performed to directly test the effect of this variant on RAD51C protein function, this suggests that disruption of this region of the protein is causative of disease. 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, susceptibility to, 3		criteria provided, single submitter	clinical testing
Counsyl	RCV000576756	SCV000677795	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2016-08-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116170	SCV000691214	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This variant causes a 3-basepair deletion at the +5 to +7 positions in intron 8 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have reported this variant to cause the skipping of exon 8 by RT-PCR of patient derived total RNA, resulting in frameshift and premature translation stop signal (PMID: 24139550, 26057125, 27616075, 28905878, 31843900). This aberrant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein lacking the functionally important nuclear localization signal (a.a. 366-370), which is required for nuclear localization and robust DNA damage response of the RAD51C protein (PMID: 12966089). This variant has been reported in four individuals affected with ovarian cancer (PMID: 24139550, 26057125, 31882575, 32957588), at least five individuals affected with breast cancer (PMID: 22538716, 27616075, 29255180, 30086788, 30257646, 32854451), as well as one individual with renal cell carcinoma (PMID: 29978187). This variant has also been identified in 3/251392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	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, susceptibility to, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194265	SCV001363657	pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-17	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.1026+5_1026+7delGTA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5 prime splicing donor site. Three publications report experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 1.6e-05 in 253704 control chromosomes. c.1026+5_1026+7delGTA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000235204	SCV001447258	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Mendelics	RCV003492508	SCV002518958	likely pathogenic	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116170	SCV002531784	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-21	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000576756	SCV002811477	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2022-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000456115	SCV004017748	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24139550, 26057125]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000456115	SCV004207913	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235204	SCV004220129	pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	The RAD51C c.1026+5_1026+7del variant has been reported in the published literature in several individuals affected with breast and/or ovarian cancer (PMIDs: 22538716 (2012), 24139550 (2013), 26057125 (2015), 26681312 (2015), 27616075 (2016), 29255180 (2017), 30086788 (2018), 30257646 (2018), 31882575 (2019), 32854451 (2020)). Functional studies have shown that this variant causes aberrant splicing including exon 8 skipping (PMIDs: 24139550 (2013), 26057125 (2015), 27616075 (2016), 28905878 (2017), 31843900 (2019)). The frequency of this variant in the general population, 0.000026 (3/113684 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
King Laboratory, University of Washington	RCV001171470	SCV001251382	pathogenic	Hereditary site-specific ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
CZECANCA consortium	RCV001271004	SCV001451816	likely pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128147	SCV003804365	likely pathogenic	Uterine corpus cancer	2023-02-21	no assertion criteria provided	clinical testing