ClinVar Miner

Submissions for variant NM_002878.4(RAD51D):c.556C>T (p.Arg186Ter)

gnomAD frequency: 0.00003  dbSNP: rs387906843
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Total submissions: 22
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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 (formerly Invitae), Labcorp 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, LLC DBA Color Health 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.
GeneDx 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, LabCorp 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.
PreventionGenetics, part of Exact Sciences 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
CeGaT Center for Human Genetics Tuebingen RCV000479705 SCV001250269 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Sema4, 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, Fulgent Genetics RCV000023220 SCV002784038 pathogenic Breast-ovarian cancer, familial, susceptibility to, 4 2021-08-04 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. 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, Revvity RCV000479705 SCV004238118 pathogenic not provided 2019-07-30 criteria provided, single submitter clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research 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, Sinai Health System 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, Sinai Health System 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-NCC-Department of Gynecologic Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College RCV002463429 SCV002605543 pathogenic Ovarian neoplasm no assertion criteria provided clinical testing

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