Submissions for variant NM_002878.4(RAD51D):c.270_271dup (p.Lys91fs)

dbSNP: rs753862052

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226442	SCV000287703	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys91Ilefs*13) 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 (rs753862052, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with male breast cancer and ovarian and breast cancer (PMID: 21822267, 28008555). ClinVar contains an entry for this variant (Variation ID: 239394). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000570770	SCV000663808	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	clinical testing	The c.270_271dupTA pathogenic mutation, located in coding exon 4 of the RAD51D gene, results from a duplication of TA at nucleotide position 270, causing a translational frameshift with a predicted alternate stop codon (p.K91Ifs*13). This mutation has been detected in multiple ovarian cancer patients as well as male and female breast cancer patients (Loveday C et al. Nat. Genet. 2011 Sep;43:879-82; Frey MK et al. Gynecol. Oncol. 2015 Nov;139:211-5; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Hirasawa A et al. Oncotarget. 2017 Nov;8:112258-112267; Wang YA et al. BMC Cancer. 2018 Mar;18:315; Eoh KJ et al. Cancer Res Treat. 2018 Jul;50:917-925). 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.
Counsyl	RCV000226442	SCV000677792	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2017-05-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570770	SCV000686437	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 4 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 reported in multiple individuals affected with breast and/or ovarian cancer (PMID: 21822267, 28008555, 29020732, 29348823, 32068069, 32359370, 35186721, 36544182). This variant also has been detected in a two breast cancer case-control studies in 15/60463 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000038) and in 3/831 cases and 2/839 unaffected individuals (PMID: 32318955). This variant has been identified in 14/251448 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.
GeneDx	RCV000657171	SCV000778892	pathogenic	not provided	2023-04-04	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; Also known as c.271_272insTA, c.330_331dupTA; This variant is associated with the following publications: (PMID: 23372765, 28495237, 21822267, 28008555, 28724667, 26296696, 29020732, 29566657, 29348823, 28522256, 30165555, 32068069, 34917121, 32107557, 30875412, 33151324, 30982232, 32566746, 32318955, 26681312, 35273153, 28888541, 36225625, 35641994, 32980694)
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030591	SCV001193728	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001030591	SCV001363871	pathogenic	Hereditary breast ovarian cancer syndrome	2021-06-21	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.270_271dupTA (p.Lys91IlefsX13) 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 6.3e-05 in 253126 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. c.270_271dupTA has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (example: Loveday_2011, Sun_2017, Zeng_2020). 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. In addition, a recent large case-control study evaluating breast cancer cases and controls and a large scale meta-analyses evaluating ovarian cancer cases and controls found a moderate risk association of RAD51D truncating variants with familial breast cancer (overall odds ratio (OR) =1.80, 95% Cis: 1.112.93, p=0.018) as well as with ovarian cancer (overall OR = 6.94, 95% CI: 5.109.44; p< 0.0001) (Dorling_2021, Suszynska_2020). Six other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000657171	SCV002063606	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000570770	SCV002534791	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000657171	SCV002550927	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000226442	SCV004017743	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 frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000226442	SCV004200429	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-03-10	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000226442	SCV005418221	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PS4_Moderate
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657171	SCV005623962	pathogenic	not provided	2024-02-02	criteria provided, single submitter	clinical testing	The RAD51D c.270_271dup (p.Lys91Ilefs*13) 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 affected with breast and/or ovarian cancer (PMIDs: 32318955 (2020), 32068069 (2020), 31780705 (2019), 30982232 (2019), 30875412 (2019), 29566657 (2018), 29020732 (2018), 29348823 (2017)). The frequency of this variant in the general population, 0.00076 (14/18394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000226442	SCV005641832	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-20	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000570770	SCV005689573	likely pathogenic	Hereditary cancer-predisposing syndrome	2025-02-04	criteria provided, single submitter	clinical testing	PVS1; PS4_SUP
China-NCC-Department of Gynecologic Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College	RCV003105831	SCV002605542	pathogenic	Ovarian neoplasm		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003165626	SCV002758306	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research