ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs754367349
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Total submissions: 11
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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
Invitae RCV000697930 SCV000826564 pathogenic Fanconi anemia complementation group O 2024-01-27 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.
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

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