ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.898C>T (p.Arg300Ter) (rs750621215)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164406 SCV000215042 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-21 criteria provided, single submitter clinical testing The p.R300* variant (also known as c.898C>T), located in coding exon 9 of the RAD51D gene, results from a C to T substitution at nucleotide position 898. This changes the amino acid from an arginine to a stop codon within coding exon 9, eliminating the last 28 amino acids from the protein. Structural analysis has revealed that this region contains a highly conserved ​ATP cap which functions to hold the ATP in place, and is likely to impact nucleoprotein filament stability (Amunugama R et al. J. Biol. Chem. 2012 Mar;287:8724-36). This alteration has been reported in numerous breast cancer patients, an ovarian cancer (endometrioid type) patient, and an unaffected 49-year-old female with one first-degree relative with breast cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Konstanta I et al. J. Hum. Genet. 2018 Nov;63:1149-1158; Song et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Sun J et al. Clin. Cancer Res. 2017 Oct 15;23:6113-6119). In addition, this amino acid position is highly conserved in available vertebrate species. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of RAD51D, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 28 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural analysis suggests that this truncated region is important for protein function. As such, this alteration is classified as likely pathogenic.
Invitae RCV000227954 SCV000287729 likely pathogenic Breast-ovarian cancer, familial 4 2020-10-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal at codon 300 located within the last 15 codons of the penultimate exon of RAD51D mRNA (p.Arg300*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 29 amino acids of the RAD51D protein. This variant is present in population databases (rs750621215, ExAC 0.01%). This variant has been reported in individuals with breast and ovarian cancer, as well as a control individual with a family history of breast cancer (PMID: 25452441, 26261251, 28724667, 29255180). Segregation studies have not been done in the reported individuals carrying this variant. This variant is also known as c.958C>T (p.Arg320*) in the literature. ClinVar contains an entry for this variant (Variation ID: 185048). This variant is expected to delete amino acid residues Arg300-Thr328 of the RAD51D protein, thereby removing the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057). Although functional studies have not been done for this particular variant, experimental studies using yeast two-hybrid analysis have shown that the region of the RAD51D protein necessary for RAD51C complexing localizes to the last ~100 amino acids (PMID: 10749867, 14704354, 19327148). The data indicates that this variant likely disrupts this important RAD51D-RAD51C interaction. 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.
GeneDx RCV000235877 SCV000292901 likely pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.898C>T at the cDNA level and p.Arg300Ter (R300X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). This variant has been identified in at least one woman with high grade ovarian cancer as well as in several women with a history of breast cancer (Couch 2015, Song 2015, Sun 2017, Konstanta 2018). Due to the position of the variant, nonsense mediated decay is not expected to occur, but it is predicted to cause loss of normal protein function through protein truncation as the last 29 amino acids are lost. The disrupted region is located within the RAD51C binding domain (Miller 2004). Based on currently available, evidence, we consider RAD51D Arg300Ter to be a likely pathogenic variant.
Mendelics RCV000709431 SCV000839173 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000227954 SCV000894109 likely pathogenic Breast-ovarian cancer, familial 4 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164406 SCV000908943 likely pathogenic Hereditary cancer-predisposing syndrome 2021-01-21 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 9 of the RAD51D gene, creating a premature translation stop signal in the penultimate coding exon. This variant is also known as c.958C>T (p.Arg320*) based on a different transcript (NM_001142571.2). The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the last 28 amino acids of the RAD51D protein, which encodes the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148). Although functional studies have not been reported for this variant, this variant is likely to disrupt RAD51D function. This variant has been reported in multiple individuals affected with breast cancer (PMID: 25452441, 28724667, 29255180, 30111881). This variant has also been reported in individuals affected with ovarian cancer and in an unaffected individual with family history of breast cancer (PMID: 26261251). This variant has been identified in 7/251356 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 Likely Pathogenic.
Mendelics RCV000227954 SCV001140407 likely pathogenic Breast-ovarian cancer, familial 4 2019-05-28 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235877 SCV001447798 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000709431 SCV001623212 likely pathogenic Hereditary breast and ovarian cancer syndrome 2021-04-30 criteria provided, single submitter clinical testing Variant summary: RAD51D c.898C>T (p.Arg300X) located in exon 9 results in a premature termination codon, predicted to cause a truncation of the encoded protein by deleting the last 29 amino acids of the RAD51D protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory. The variant allele was found at a frequency of 2.8e-05 in 251356 control chromosomes. c.898C>T has been widely reported in the literature in individuals affected with tubo-ovarian carcinoma (TOC) and breast cancer (example, Yang_2020; Fostira_2020). One of these ascertained studies provided age-specific risk for TOC for women with pathogenic variants in RAD51D and also confirmed that pathogenic variants in RAD51D confer a moderate risk for breast cancer (Yang_2020). These data indicate that the variant is 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000227954 SCV001737459 likely pathogenic Breast-ovarian cancer, familial 4 2021-03-31 criteria provided, single submitter clinical testing The RAD51D c.898C>T (p.Arg300Ter) change is a nonsense variant that is predicted to cause premature protein truncation. The variant is not expected to result in nonsense mediated decay, but it is predicted to cause loss of normal protein function through removal of the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148). This variant has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-33428225-G-A?dataset=gnomad_r2_1). This variant has been reported in individuals with breast cancer (PMID: 30111881, 30165555, 25452441, 28724667), ovarian cancer (PMID: 26261251), and a control individual with a family history of breast cancer (PMID: 26261251). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1, PS4.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356854 SCV001552126 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The RAD51D p.Arg300* variant was identified in 3 of 10506 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer or invasive epithelial ovarian cancer (Couch 2015, Song 2015). The variant was also identified in dbSNP (ID: rs750621215) as "With Likely pathogenic allele ", and in ClinVar (classified as likely pathogenic by Invitae, Ambry Genetics and GeneDx). The variant was not identified in the Cosmic database. The variant was identified in control databases in 7 of 246158 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111630 chromosomes (freq: 0.00003), East Asian in 3 of 17248 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, and Finnish populations. The c.898C>T variant leads to a premature stop codon at position 300, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the RAD51D gene are an established mechanism of disease in RAD51D-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.