Submissions for variant NM_002878.4(RAD51D):c.898C>T (p.Arg300Ter)

gnomAD frequency: 0.00002  dbSNP: rs750621215

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164406	SCV000215042	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-12-06	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. This alteration occurs at the 3' terminus of theRAD51D gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 28 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). 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 identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Song et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Sun J et al. Clin. Cancer Res. 2017 Oct 15;23:6113-6119; Konstanta I et al. J. Hum. Genet. 2018 Nov;63:1149-1158; Gomez-Puerto D et al. Front Oncol, 2022 Sep;12:963728; Yao H et al. BMC Cancer, 2022 Dec;22:1337). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227954	SCV000287729	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg300*) in the RAD51D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the RAD51D protein. This variant is present in population databases (rs750621215, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with personal and/or family history of breast cancer and/or ovarian cancer (PMID: 25452441, 26261251, 28724667, 29255180, 32885271). This variant is also known as c.958C>T (p.Arg320*). 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	2024-04-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 29 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Observed in individuals with a personal or family history including breast, ovarian, and/or prostate cancer (PMID: 25452441, 26261251, 28724667, 30111881, 34887416, 35710434, 36095024, 36495689); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(R188X); This variant is associated with the following publications: (PMID: 25344691, 29255180, 25452441, 26261251, 28152038, 28724667, 30165555, 30111881, 31589614, 33471991, 31300551, 32885271, 32107557, 34923718, 33804961, 36185283, 36544182, 30675318, 31341520, 33858678, 35171259, 35710434, 35014770, 35186721, 36243179, 36113475, 34887416, 36095024, 38028594, 33047316, 35273153, 37065479, 36495689, 14704354, 21111057, 19327148)
Fulgent Genetics, Fulgent Genetics	RCV000227954	SCV000894109	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164406	SCV000908943	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-25	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. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported for this variant, it is expected to disrupt the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148) and adversely impact RAD51D protein function. This variant has been observed in at least three individuals with ovarian cancer (PMID: 26261251, 33858678, 35186721, 36544182). It has also been reported in over ten individuals with breast cancer (PMID: 25452441, 28724667, 29255180, 30111881, 31300551, 32885271, 33471991, 36185283) and in several control subjects unaffected with cancer (PMID: 26261251, 33471991). This variant has been identified in 7/251356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mendelics	RCV000227954	SCV001140407	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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 ovarian cancer syndrome	2023-11-16	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. 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. The following publications have been ascertained in the context of this evaluation (PMID: 31300551, 32107557). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000227954	SCV001737459	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798583	SCV002043221	likely pathogenic	Breast and/or ovarian cancer	2021-08-20	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000235877	SCV002502728	likely pathogenic	not provided	2021-08-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164406	SCV002534868	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	curation
Baylor Genetics	RCV000227954	SCV004200381	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235877	SCV004220188	likely pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This nonsense variant is predicted to cause the premature termination of RAD51D protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 35710434 (2022), 36185283 (2022), 32885271 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared), 31300551 (2020), 30111881 (2018), 29255180 (2017), 28724667 (2017), 26261251 (2015), 25452441 (2015)), prostate cancer (PMID: 36095024 (2022)), pancreatic cancer (PMID: 35171259 (2022)), and lung cancer (PMID: 35273153 (2022)). This variant has additionally been observed in reportedly healthy individuals (PMIDs: 33804961 (2021), 34887416 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared), 32906206 (2020), 26261251 (2015)). The frequency of this variant in the general population, 0.00016 (3/18392 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000709431	SCV004228142	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000227954	SCV004931921	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2023-12-19	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.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000235877	SCV005200509	likely pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. female patient with breast cancer
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.
China-NCC-Department of Gynecologic Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College	RCV002463438	SCV002754422	pathogenic	Ovarian neoplasm		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162688	SCV002758189	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research