Submissions for variant NM_058216.3(RAD51C):c.774del (p.Thr259fs)

gnomAD frequency: 0.00004  dbSNP: rs754367349

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484016	SCV000566828	likely pathogenic	not provided	2021-11-19	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; Observed in individuals with a personal and family history of RAD51C-related cancers in published literature (Romero 2011, Vuorela 2011, Cunningham 2014, Song 2015, Nguyen-Dumont 2020); This variant is associated with the following publications: (PMID: 23117857, 26261251, 21616938, 25086635, 24800917, 21537932, 21750962, 22451500, 24504028, 21990120, 20400964, 32338768, 25470109)
Counsyl	RCV000576452	SCV000677785	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581899	SCV000691266	pathogenic	Hereditary cancer-predisposing syndrome	2017-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697930	SCV000826564	pathogenic	Fanconi anemia complementation group O	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr259Leufs*4) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is present in population databases (rs754367349, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 21537932, 21750962, 26261251). ClinVar contains an entry for this variant (Variation ID: 419188). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000581899	SCV001189230	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-13	criteria provided, single submitter	clinical testing	The c.774delT pathogenic mutation, located in coding exon 5 of the RAD51C gene, results from a deletion of one nucleotide at nucleotide position 774, causing a translational frameshift with a predicted alternate stop codon (p.T259Lfs*4). This mutation has been reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer and has also been proposed as a Swedish founder mutation (Romero A et al. Breast Cancer Res. Treat. 2011 Oct;129:939-46; Vuorela M et al. Breast Cancer Res. Treat. 2011 Dec;130:1003-10; Osorio A et al. Hum. Mol. Genet., 2012 Jul;21:2889-98; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). 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.
Division of Medical Genetics, University of Washington	RCV001250429	SCV001424790	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2019-09-10	criteria provided, single submitter	clinical testing	This variant leads to a translational frameshift and the introduction of a premature termination codon four residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of RAD51C is a well-established mechanism of disease for increased ovarian cancer risk [Romero 2011, Vuorela 2011, Song 2015]. This variant has been reported in individuals with breast and ovarian cancer [Meindl 2010, Thompson 2012, Rashid 2014]. This variant has a combined allele frequency of 0.000045 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as likely pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000484016	SCV001450059	pathogenic	not provided	2019-07-24	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000484016	SCV002551138	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001250429	SCV004019971	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000484016	SCV005197322	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000581899	SCV005689566	likely pathogenic	Hereditary cancer-predisposing syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000484016	SCV001365275	pathogenic	not provided	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.
BRCAlab, Lund University	RCV001250429	SCV002589014	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2022-08-26	no assertion criteria provided	clinical testing