Total submissions: 22
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000129358 | SCV000184122 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-11-22 | criteria provided, single submitter | clinical testing | The p.R186* pathogenic mutation (also known as c.556C>T), located in coding exon 6 of the RAD51D gene, results from a C to T substitution at nucleotide position 556. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been described in several breast and/or ovarian cancer patients (Loveday C et al. Nat. Genet. 2011 Sep;43:879-82; Osher D et al. Br. J. Cancer. 2012 Apr;106:1460-3; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Byers H et al. Eur. J. Hum. Genet. 2016 Nov;24:1591-1597; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This mutation has also been reported in an individual diagnosed with grade 2 papillary serous cystadenocarcinoma, in a pre-menopausal breast cancer patient who underwent oophorectomy and was found to have serous tubal intraepithelial cancer, and in prostate cancer patients (Thompson E et al. PLoS One. 2013;8:e54772; Harvey LFB et al. J Minim Invasive Gynecol. 2017 Aug;[Epub ahead of print]; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
Labcorp Genetics |
RCV000023220 | SCV000287716 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg186*) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is present in population databases (rs387906843, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with ovarian and breast cancer (PMID: 21822267, 22415235, 23372765, 25445424, 26261251). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30285). For these reasons, this variant has been classified as Pathogenic. |
Counsyl | RCV000023220 | SCV000488558 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2016-06-09 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000129358 | SCV000537684 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-17 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 6 of the RAD51D gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with ovarian cancer (PMID: 21822267, 22415235, 23372765, 26261251, 32068069, 36544182), breast cancer (PMID: 21822267, 22415235, 27153395, 27273131), and in an individual affected with endometrial and serous tubal intraepithelial cancer (PMID: 28821472). This variant has also been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000017). This variant has been identified in 12/280688 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
Gene |
RCV000479705 | SCV000567797 | pathogenic | not provided | 2023-09-13 | criteria provided, single submitter | clinical testing | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27273131, 32242007, 30165555, 32986223, 28888541, 21822267, 25445424, 19383352, 22415235, 26328243, 26261251, 27153395, 23372765, 29560538, 28724667, 28821472, 26057125, 28152038, 30111881, 28591191, 30980208, 26689913, 32068069, 32885271, 32338768, 32107557, 35641994, 33804961, 32191290, 36346689, 36544182, 36169650, 32359370, 33471991, 32295079) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000589947 | SCV000698107 | pathogenic | Hereditary breast ovarian cancer syndrome | 2016-09-30 | criteria provided, single submitter | clinical testing | Variant summary: The RAD51D c.556C>T (p.Arg186X) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51D protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation located downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg232X). Mutation taster predicts a damaging outcome for this variant. This variant was found in 6/115838 control chromosomes at a frequency of 0.0000518, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). It was reported in several breast and ovarian cancer patients indicating causality. In addition multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
Prevention |
RCV000479705 | SCV000806579 | pathogenic | not provided | 2016-11-02 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000479705 | SCV000889827 | pathogenic | not provided | 2024-02-27 | criteria provided, single submitter | clinical testing | The RAD51D c.556C>T (p.Arg186*) variant causes the premature termination of RAD51D protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 36544182 (2022), 35641994 (2022), 32068069 (2020), 26261251 (2015)), breast cancer (PMID: 32885271 (2021), 30980208 (2019), 30165555 (2018), 23372765 (2013)), prostate cancer (PMID: 32338768 (2020)) and osteosarcoma (PMID: 32191290 (2020)). The frequency of this variant in the general population, 0.00059 (6/10256 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. |
Mendelics | RCV000023220 | SCV001140415 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000479705 | SCV001250269 | pathogenic | not provided | 2019-12-01 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000129358 | SCV002534827 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-03-02 | criteria provided, single submitter | curation | |
MGZ Medical Genetics Center | RCV000023220 | SCV002580825 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2022-03-08 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000023220 | SCV002784038 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2021-08-04 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000023220 | SCV004017750 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2023-04-06 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
Baylor Genetics | RCV000023220 | SCV004208097 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2024-03-14 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000479705 | SCV004238118 | pathogenic | not provided | 2019-07-30 | criteria provided, single submitter | clinical testing | |
Cancer Genomics Group, |
RCV000589947 | SCV005045664 | pathogenic | Hereditary breast ovarian cancer syndrome | 2023-03-27 | criteria provided, single submitter | research | |
OMIM | RCV000023220 | SCV000044511 | risk factor | Breast-ovarian cancer, familial, susceptibility to, 4 | 2011-08-07 | no assertion criteria provided | literature only | |
CZECANCA consortium | RCV001271049 | SCV001451868 | pathogenic | Breast and/or ovarian cancer | 2019-06-11 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV000023220 | SCV001550804 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | no assertion criteria provided | clinical testing | The RAD51D p.Arg186X variant was identified in 7 of 15516 proband chromosomes (frequency: 0.00045) from individuals or families with breast and/or ovarian cancer or at high risk of ovarian cancer and was not identified in 7744 control chromosomes from healthy individuals (Loveday 2011, Song 20015, Thompson 2013, Keen-Kim 2017, Osher 2012). The variant was also identified in dbSNP (ID: rs387906843) as “With Pathogenic allele”, ClinVar (classified 5x as pathogenic by Ambry Genetics, Invitae, Counsyl, Color Genomics and GeneDx; classified as risk factor by OMIM), Clinvitae (same references as ClinVar), databases. The variant was not identified in the COSMIC database. The variant was identified in control databases in 8 of 275060 chromosomes at a frequency of 0.00003 in the following populations: Ashkenazi Jewish in 4 of 10036 chromosomes (freq. 0.0004); European non-Finnish in 4 of 125824 chromosomes (freq. 0.00003), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). This variant was identified in 2 Canadian individuals with ovarian cancer from the same family, both of whom demonstrated loss of wild-type allele in DNA extracted from tumour cells (Osher 2012). In a 3-generation pedigree segregating ovarian cancer and breast cancer this variant was found in 4 members of the same family (Loveday 2011). The proband had ovarian cancer at age 38; the variant was also confirmed in her sister who had breast cancer at age 39, and two aunts who had breast cancer at age 58 and age 53. Four other relatives on whom no molecular testing could be done died of ovarian cancer ranging in age from 49 to 65 years. Loss of function variants of the RAD51D gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. | |
Department of Pathology and Laboratory Medicine, |
RCV001357904 | SCV001553504 | pathogenic | Malignant tumor of breast | no assertion criteria provided | clinical testing | The RAD51D p.Arg186X variant was identified in 7 of 15516 proband chromosomes (frequency: 0.00045) from individuals or families with breast and/or ovarian cancer or at high risk of ovarian cancer and was not identified in 7744 control chromosomes from healthy individuals (Loveday 2011, Song 20015, Thompson 2013, Keen-Kim 2017, Osher 2012). The variant was also identified in dbSNP (ID: rs387906843) as “With Pathogenic allele”, ClinVar (classified 5x as pathogenic by Ambry Genetics, Invitae, Counsyl, Color Genomics and GeneDx; classified as risk factor by OMIM), Clinvitae (same references as ClinVar), databases. The variant was not identified in the COSMIC database. The variant was identified in control databases in 8 of 275060 chromosomes at a frequency of 0.00003 in the following populations: Ashkenazi Jewish in 4 of 10036 chromosomes (freq. 0.0004); European non-Finnish in 4 of 125824 chromosomes (freq. 0.00003), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). This variant was identified in 2 Canadian individuals with ovarian cancer from the same family, both of whom demonstrated loss of wild-type allele in DNA extracted from tumour cells (Osher 2012). In a 3-generation pedigree segregating ovarian cancer and breast cancer this variant was found in 4 members of the same family (Loveday 2011). The proband had ovarian cancer at age 38; the variant was also confirmed in her sister who had breast cancer at age 39, and two aunts who had breast cancer at age 58 and age 53. Four other relatives on whom no molecular testing could be done died of ovarian cancer ranging in age from 49 to 65 years. Loss of function variants of the RAD51D gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. | |
China- |
RCV002463429 | SCV002605543 | pathogenic | Ovarian neoplasm | no assertion criteria provided | clinical testing |