Submissions for variant NM_002878.4(RAD51D):c.748del (p.His250fs)

dbSNP: rs587780105

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212968	SCV000149729	pathogenic	not provided	2024-02-21	criteria provided, single submitter	clinical testing	Frameshift 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: 26681312, 21822267, 25452441, 25445424, 26261251, 28152038, 31948886, 32107557, 28888541, 33804961, 35980532, 35534704, 33471991, 34326862, 33008098)
Ambry Genetics	RCV000115820	SCV000185265	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-17	criteria provided, single submitter	clinical testing	The c.748delC pathogenic mutation, located in coding exon 9 of the RAD51D gene, results from a deletion of one nucleotide at nucleotide position 748, causing a translational frameshift with a predicted alternate stop codon (p.H250Tfs*2). This variant has been detected in multiple breast and/or ovarian cancer cohorts (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Susswein LR et al. Genet Med, 2016 08;18:823-32; Barbosa A et al. Cancers (Basel), 2020 Sep;12), as well as in a prostate cancer patient (Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230). In one study, this variant was reported in 2 of 60466 breast cancer cases and in 2 of 53461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000465960	SCV000551352	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His250Thrfs*2) 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 (rs587780105, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 25452441, 26261251). ClinVar contains an entry for this variant (Variation ID: 127894). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586494	SCV000698096	pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The RAD51D c.748delC (p.His250Thrfs) 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. One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple HBOC patients and is absent in 120950 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115820	SCV001353826	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 9 of the RAD51D gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in five individuals affected with ovarian cancer, including three individuals from the same family (PMID: 26261251, 33008098). This variant has been reported in an individual with triple-negative breast cancer (PMID: 25452441). This variant has been identified in 1/251058 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798344	SCV002043220	likely pathogenic	Breast and/or ovarian cancer	2019-11-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000465960	SCV004200354	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000465960	SCV004931166	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212968	SCV005623970	pathogenic	not provided	2024-04-17	criteria provided, single submitter	clinical testing	The RAD51D c.748del (p.His250Thrfs*2) variant alters the translational reading frame of the RAD51D mRNA and causes the premature termination of RAD51D protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMIDs: 26261251 (2015), 26681312 (2015), 33008098 (2020)), breast cancer (PMIDs: 25452441 (2015), 26681312 (2015), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D)), and prostate cancer (PMID: 31948886 (2020)). The frequency of this variant in the general population, 0.000004 (1/251058 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.