Submissions for variant NM_058216.3(RAD51C):c.577C>T (p.Arg193Ter)

gnomAD frequency: 0.00004  dbSNP: rs200293302

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129056	SCV000183755	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-03	criteria provided, single submitter	clinical testing	The p.R193* pathogenic mutation (also known as c.577C>T), located in coding exon 4 of the RAD51C gene, results from a C to T substitution at nucleotide position 577. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple families of different ethnicities with breast and/or ovarian cancer (Loveday C et al. Nat. Genet., 2012 Apr;44:475-6; author reply 476; Kushnir A et al. Breast Cancer Res Treat, 2012 Dec;136:869-74; Coulet F et al. Clin. Genet., 2013 Apr;83:332-6; Pennington KP et al. Clin Cancer Res, 2014 Feb;20:764-75; Blanco A et al. Breast Cancer Res Treat, 2014 Aug;147:133-43; Sopik V et al. Clin Genet, 2015 Oct;88:303-12; Song H et al. J Clin Oncol, 2015 Sep;33:2901-7; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Jønson L et al. Breast Cancer Res Treat, 2016 Jan;155:215-22; Susswein LR et al. Genet Med, 2016 08;18:823-32; Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Li N et al. J Natl Cancer Inst, 2019 12;111:1332-1338; Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in a patient with cutaneous melanoma and in an individual with multifocal paragangliomas and B-cell lymphocytosis with a family history of ovarian and colon cancer (Goyal A et al. JAAD Case Rep, 2019 Mar;5:240-241; Aoude LG et al. Sci Rep, 2020 10;10(1):17687). This alteration was shown to be susceptible to PARP inhibitors in mice, demonstrating loss of homologous repair pathway function (Kondrashova O et al. Cancer Discov, 2017 09;7:984-998). 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	RCV000212943	SCV000211615	pathogenic	not provided	2023-04-20	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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22538716, 26740214, 25086635, 26261251, 23117857, 28588062, 22725699, 26720728, 25470109, 26681312, 26976419, 29093764, 29409816, 26689913, 32658311, 31589614, 28888541, 29922827, 34026625, 33077847, 33804961, 35626031, 34308104, 33999380)
Invitae	RCV000203684	SCV000260761	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.Arg193*) 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 (rs200293302, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22538716, 22725699, 25086635, 26261251, 26740214). ClinVar contains an entry for this variant (Variation ID: 140849). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129056	SCV000292164	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the RAD51C 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 observed in individuals affected with ovarian cancer (PMID: 22538716, 22725699, 26261251) and breast cancer (PMID: 25086635, 26740214, 26976419, 30949688, 32658311, 33471991). This variant has been identified in 10/251204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000576579	SCV000677771	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2017-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590531	SCV000699816	pathogenic	Hereditary breast ovarian cancer syndrome	2017-07-14	criteria provided, single submitter	clinical testing	Variant summary: The RAD51C c.577C>T (p.Arg193X) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51C protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/120882 control chromosomes at a frequency of 0.0000414, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). Multiple publications have cited the variant in affected individuals, including a family that the variant cosegregated with disease (Blanco_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000576579	SCV000893460	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778126	SCV000914251	pathogenic	RAD51C-Related Disorders	2019-04-05	criteria provided, single submitter	clinical testing	The RAD51C c.577C>T (p.Arg193Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg193Ter variant has been reported in at least five studies in which it is found in a heterozygous state in seven individuals diagnosed with ovarian cancer, two of whom are related (Loveday et al. 2012; Coulet et al. 2013; Blanco et al. 2014; Song et al. 2015; Jonson et al. 2016). The p.Arg193Ter variant was also reported in a heterozygous state in two unaffected individuals who may yet be too young to develop disease (one individual was 25 years old and the other is of unknown age). All of these individuals have a family history of breast and/or ovarian cancer and are negative for variants in the BRCA1 and BRCA2 genes. The p.Arg193Ter variant was absent from 3,928 controls and is reported at a frequency of 0.00012 in the Latino population of the Genome Aggregation Database. Although the p.Arg193Ter variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of disease penetrance and prevalence estimates. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg193Ter variant is classified as pathogenic for RAD51C-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212943	SCV001446729	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000212943	SCV001468021	likely pathogenic	not provided	2020-08-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129056	SCV002531829	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-06	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288621	SCV002580532	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2021-12-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288621	SCV004019910	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 termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV002288621	SCV004207957	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-08-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212943	SCV004220149	pathogenic	not provided	2021-09-14	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of RAD51C protein synthesis. In addition, it has been reported in individuals/families with breast and/or ovarian cancer in the published literature (PMID: 32658311 (2021), 26976419 (2016), 26740214 (2016), 25086635 (2014), 22725699 (2013), 22538716 (2012)). Based on the available information, this variant is classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554248	SCV001774817	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV002288621	SCV002589011	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2022-08-26	no assertion criteria provided	clinical testing