Submissions for variant NM_058216.3(RAD51C):c.709C>T (p.Arg237Ter)

gnomAD frequency: 0.00001  dbSNP: rs770637624

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165947	SCV000216703	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-08	criteria provided, single submitter	clinical testing	The p.R237* pathogenic mutation (also known as c.709C>T), located in coding exon 5 of the RAD51C gene, results from a C to T substitution at nucleotide position 709. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been observed in Spanish hereditary breast and/or ovarian cancer families (Blanco A et al. Breast Cancer Res. Treat. 2014 Aug;147:133-43; Tavera-Tapia A et al. Breast Cancer Res. Treat. 2017 02;161:597-604). It was also reported in a study of 4439 patients with ovarian cancer (Carter NJ et al. Gynecol. Oncol. 2018 12;151:481-488). In a study of men with metastatic prostate cancer, who were unselected for family history of cancer or age at diagnosis, this alteration was identified in 1/692 men (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). 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.
Invitae	RCV000233212	SCV000291234	pathogenic	Fanconi anemia complementation group O	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg237*) 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 (rs770637624, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with thyroid and ovarian cancer (PMID: 25086635). ClinVar contains an entry for this variant (Variation ID: 186364). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165947	SCV000537645	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 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 reported in individuals affected with ovarian cancer (PMID: 25086635, 30322717, 33008098) and breast cancer (PMID: 31300551). This variant also has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000056). This variant has been identified in 4/251374 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.
GeneDx	RCV000484844	SCV000567973	pathogenic	not provided	2022-12-06	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: 29922827, 28888541, 25086635, 27433846, 28024868, 27913932, 27806231, 30151275, 29625052, 31784482, 32659967, 31589614, 35264596, 31300551, 30322717, 36232793)
Counsyl	RCV000576766	SCV000677818	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2017-04-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000709509	SCV000839333	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484844	SCV000888602	pathogenic	not provided	2018-07-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000233212	SCV001140719	pathogenic	Fanconi anemia complementation group O	2019-05-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000233212	SCV001369037	pathogenic	Fanconi anemia complementation group O	2019-05-13	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000709509	SCV001467826	pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-11	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.709C>T (p.Arg237X) 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 1.6e-05 in 251374 control chromosomes (gnomAD). c.709C>T has been reported in the literature in individuals affected with e.g. ovarian-, breast- and prostate cancer, and some of these patients had a strong family history or early onset of disease (e.g. Blanco_2014, Pritchard_2016, Carter_2018, Fostira_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000233212	SCV002019634	pathogenic	Fanconi anemia complementation group O	2019-01-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000576766	SCV002803957	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2022-04-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001356354	SCV004019935	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	RCV001356354	SCV004207960	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-08-24	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000484844	SCV001365272	pathogenic	not provided	2019-12-23	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Florentia Fostira.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356354	SCV001551499	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3		no assertion criteria provided	clinical testing	The RAD51C p.Arg237X variant was identified in 3 of 1872 proband chromosomes (frequency: 0.002) from individuals or families with breast, ovarian, or gastric cancer (Blanco 2014, Sahasrabudhe 2017, Tavera-Tapia 2017). The variant was also identified in the following databases: dbSNP (ID: rs770637624) as "With Pathogenic allele", ClinVar (5x pathogenic), and Clinvitae (3x pathogenic). The variant was not identified in Cosmic, MutDB, or the LOVD 3.0 databases. The variant was identified in control databases in 4 of 246148 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 3 of 111606 chromosomes (freq: 0.00003) and East Asian in 1 of 17248 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The c.709C>T variant leads to a premature stop codon at position 237 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the RAD51C gene are an established mechanism of disease and this is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554261	SCV001774861	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162706	SCV002758507	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research