ClinVar Miner

Submissions for variant NM_002878.4(RAD51D):c.694C>T (p.Arg232Ter)

gnomAD frequency: 0.00004  dbSNP: rs587780104
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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212965 SCV000149728 pathogenic not provided 2023-05-26 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); Observed in individuals with RAD51D-related cancers (Gutierrez-Enriquez et al., 2014; Wickramanayake et al., 2012; Janatova et al., 2015; Gonzalez-Rivera et al., 2016; Lilyquist et al., 2017; Tedaldi et al., 2017; Sanchez-Bermudez et al., 2018; Suszynska et al., 2020; Hauke et al., 2021); This variant is associated with the following publications: (PMID: 28423363, 28985766, 25445424, 24130102, 22986143, 26057125, 26720728, 27083178, 26681312, 29409816, 29470806, 24240112, 31589614, 32295079, 26689913, 30306255, 32318955, 32107557, 32359370, 29522266, 32980694, 34923718, 28888541, 35264596, 35565380, 33804961, 34308104)
Ambry Genetics RCV000115819 SCV000185867 pathogenic Hereditary cancer-predisposing syndrome 2022-07-20 criteria provided, single submitter clinical testing The p.R232* pathogenic mutation (also known as c.694C>T), located in coding exon 8 of the RAD51D gene, results from a C to T substitution at nucleotide position 694. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been identified in several patients diagnosed with ovarian carcinoma with a family history of breast and/or ovarian cancer (Wickramanayake A et al. Gynecol. Oncol. 2012 Dec;127:552-5; Guti&eacute;rrez-Enr&iacute;quez S et al. Int. J. Cancer. 2014 May;134:2088-97; S&aacute;nchez-Berm&uacute;dez AI et al. Eur J Med Genet 2018 Jun;61:355-361). It was also observed in two Czech women with high-grade serous adenocarcinoma diagnosed under the age of 45 with no family history of malignancy; in one woman with a personal history of triple negative breast cancer; and in one woman with a personal history of DCIS at age 47 and ovarian cancer at age 54 (Janatova M et al. PLoS ONE. 2015 Jun;10:e0127711; Gonzalez-Rivera M et al. Breast Cancer Res. Treat. 2016 04;156:507-515; Tedaldi G et al. Oncotarget. 2017 Jul;8:47064-4707). One study has estimated ovarian cancer risk for this variant (OR 16.07, 95% of 5.12-50.46; p value <0.0001) (Suszynska M et al. J Ovarian Res, 2020 May;13:50). 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.
Color Diagnostics, LLC DBA Color Health RCV000115819 SCV000292163 pathogenic Hereditary cancer-predisposing syndrome 2022-08-15 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 8 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 individuals affected with ovarian cancer (PMID: 22986143, 24130102, 26057125, 28423363). In a large breast cancer case-control study, this variant was identified in 12/60454 cases and 5/53456 controls; OR=2.122 (95%CI 0.748 to 6.024); p-value=0.223 (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51D_000003). This variant has been identified in 4/277224 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.
Counsyl RCV000410860 SCV000488995 pathogenic Breast-ovarian cancer, familial, susceptibility to, 4 2016-08-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000410860 SCV000551331 pathogenic Breast-ovarian cancer, familial, susceptibility to, 4 2024-01-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg232*) 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 (rs587780104, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22986143, 24130102, 26057125, 26681312, 27083178, 28423363). ClinVar contains an entry for this variant (Variation ID: 127893). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586822 SCV000698111 pathogenic Hereditary breast ovarian cancer syndrome 2019-04-04 criteria provided, single submitter clinical testing Variant summary: RAD51D c.694C>T (p.Arg232X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.748delC, p.His250fsX2). The variant allele was found at a frequency of 1.8e-05 in 274154 control chromosomes. c.694C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Wickramanayake_2012, Gutierrez-Enriquez_2014, Janatova_2015, Gonzalez-Rivera_2016, Tedaldi_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000586822 SCV000839180 pathogenic Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212965 SCV000889830 pathogenic not provided 2018-03-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000410860 SCV000894110 pathogenic Breast-ovarian cancer, familial, susceptibility to, 4 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000410860 SCV001440050 pathogenic Breast-ovarian cancer, familial, susceptibility to, 4 2024-11-05 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4_MOD,PM2_SUP
CeGaT Center for Human Genetics Tuebingen RCV000212965 SCV001961679 pathogenic not provided 2024-04-01 criteria provided, single submitter clinical testing RAD51D: PVS1, PM2, PS4:Moderate
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000212965 SCV002010052 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115819 SCV002534844 pathogenic Hereditary cancer-predisposing syndrome 2021-07-16 criteria provided, single submitter curation
MGZ Medical Genetics Center RCV000410860 SCV002580679 pathogenic Breast-ovarian cancer, familial, susceptibility to, 4 2022-01-31 criteria provided, single submitter clinical testing
Human Genetics Bochum, Ruhr University Bochum RCV002463640 SCV002758607 pathogenic Colorectal cancer 2022-01-04 criteria provided, single submitter clinical testing ACMG criteria used to clasify this variant: PVS1, PS4, PM2
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital RCV003313779 SCV004012919 likely pathogenic Diffuse midline glioma, H3 K27-altered 2020-10-08 criteria provided, single submitter research
Myriad Genetics, Inc. RCV000410860 SCV004017753 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 RCV000410860 SCV004208076 pathogenic Breast-ovarian cancer, familial, susceptibility to, 4 2024-03-28 criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000410860 SCV005417194 pathogenic Breast-ovarian cancer, familial, susceptibility to, 4 criteria provided, single submitter clinical testing PM2_Supporting+PVS1+PS4_Moderate
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785237 SCV000923805 pathogenic Ovarian neoplasm 2018-12-01 no assertion criteria provided research
CZECANCA consortium RCV001271051 SCV001451870 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000212965 SCV001959919 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000212965 SCV001973407 pathogenic not provided no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003162542 SCV002758191 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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