Submissions for variant NM_002878.4(RAD51D):c.757C>T (p.Arg253Ter)

dbSNP: rs137886232

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130349	SCV000185200	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-25	criteria provided, single submitter	clinical testing	The p.R253* pathogenic mutation (also known as c.757C>T), located in coding exon 9 of the RAD51D gene, results from a C to T substitution at nucleotide position 757. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation was first reported in two affected sisters from a breast/ovarian cancer kindred (Loveday C et al. Nat. Genet. 2011; 43:879-82). It has also been identified in two unrelated individuals with ovarian cancer (Norquist BM et al. JAMA Oncol 2016 Apr;2(4):482-90), in three unrelated patients from a cohort of 7657 unselected BRCA1/2 mutation negative breast cancer patients from China (Chen X et al. Ann Oncol, 2018 10;29:2046-2051), and in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119). 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.
GeneDx	RCV000235264	SCV000292680	pathogenic	not provided	2020-12-18	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 a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21822267, 24130102, 26720728, 28724667, 25445424, 30165555, 30733081, 32601921)
Counsyl	RCV000023223	SCV000488562	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2016-06-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130349	SCV000537654	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 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 reported in individuals affected with ovarian cancer (PMID: 36537080, 36544182, 36685941) and/or breast cancer (PMID: 21822267, 32107557). This variant has been identified in 4/251138 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000023223	SCV000771509	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg253*) 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 (rs137886232, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 21822267, 26720728, 28724667). ClinVar contains an entry for this variant (Variation ID: 30288). For these reasons, this variant has been classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235264	SCV002010051	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000023223	SCV004017764	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000023223	SCV004176594	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2023-03-01	criteria provided, single submitter	clinical testing	The stop gained c.757C>T (p.Arg253Ter) variant has been reported in multiple individuals affected with {Breast-ovarian cancer (Yao H et al. 2022; Chen X et al. 2018; Loveday C et al. 2011). The p.Arg253Ter variant has allele frequency 0.002% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The nucleotide change c.757C>T in RAD51D is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000023223	SCV004208072	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-22	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000023223	SCV005417105	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Moderate
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000023223	SCV005873604	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2022-01-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237406	SCV005888210	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-16	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.757C>T (p.Arg253X) 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. The variant allele was found at a frequency of 1.6e-05 in 251138 control chromosomes. c.757C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Loveday_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21822267). ClinVar contains an entry for this variant (Variation ID: 30288). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000023223	SCV000044514	risk factor	Breast-ovarian cancer, familial, susceptibility to, 4	2011-08-07	no assertion criteria provided	literature only
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554259	SCV001774864	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000023223	SCV002589015	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2022-08-26	no assertion criteria provided	clinical testing
China-NCC-Department of Gynecologic Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College	RCV002463349	SCV002754421	pathogenic	Ovarian carcinoma		no assertion criteria provided	clinical testing