Submissions for variant NM_058216.3(RAD51C):c.93del (p.Phe32fs)

dbSNP: rs730881942

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212931	SCV000211643	pathogenic	not provided	2023-05-01	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; This variant is associated with the following publications: (PMID: 23176254, 27806231, 25470109, 28152038, 21616938, 23117857, 24800917, 27433846, 26681312, 28874143, 28802053, 26556299, 26689913, 32107557, 34923718, 35053526, 35626031, 29922827, 28888541)
Ambry Genetics	RCV000160936	SCV000215256	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-31	criteria provided, single submitter	clinical testing	The c.93delG pathogenic mutation, located in coding exon 1 of the RAD51C gene, results from a deletion of one nucleotide at position 93, causing a translational frameshift with a predicted alternate stop codon (p.F32Sfs*8). This mutation has been identified in a Finnish breast/ovarian cancer kindred as well as multiple ovarian cancer only families to date (Pelttari LM et al. Hum. Mol. Genet. 2011 Aug;20:3278-88). This same group did not find the c.93delG alteration in a group of 1083 prostate cancer patients and 802 colorectal cancer patients, leading the authors to conclude that this mutation does not predispose to prostate or colorectal cancer (Pelttari LM et al. BMC Cancer. 2012;12:552). In a different prostate cancer cohort, this alteration was identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). In addition, this alteration was identified in 2/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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	RCV000205375	SCV000259467	pathogenic	Fanconi anemia complementation group O	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe32Serfs*8) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer, prostate cancer (PMID: 21616938, 27433846). It is commonly reported in individuals of Finnish ancestry (PMID: 21616938, 24800917, 27433846). ClinVar contains an entry for this variant (Variation ID: 182847). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000576723	SCV000677786	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2017-06-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160936	SCV000691291	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-20	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 1 of the RAD51C 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 an individual affected with familial ovarian cancer and another individual affected breast cancer with multiple relatives affected with breast or ovarian cancer (PMID: 21616938). This variant has also been observed in an individual with prostate cancer (PMID: 27433846). This variant has been identified in 13/282860 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587817	SCV000699829	pathogenic	Hereditary breast ovarian cancer syndrome	2017-11-22	criteria provided, single submitter	clinical testing	Variant summary: The RAD51C c.93delG (p.Phe32SerfsX8) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 15/250416 control chromosomes at a frequency of 0.0000599, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). This variant has also been reported in multiple families and individuals with breast and/or ovarian cancer and based on haplotype analysis authors concluded that it is likely a founder mutation in the Finnish population that is associated with moderate-to-high risk susceptibility for ovarian cancer (Pelttari 2011). The founder effect can also explain the higher occurrence of the variant in this population (gnomAD 5/22298 Finnish European). The variant was also found in a patient with ovarian cancer in a different population (Susswein 2016). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.97C>T (p.Gln33X), c.397C>T (p.Gln133X), c.577C>T (p.Arg193X)). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212931	SCV001134795	pathogenic	not provided	2019-06-13	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of RAD51C protein synthesis. In addition, it has been reported in affected individuals with breast, ovarian and prostate cancer in the published literature (PMIDs: 21616938 (2011), 24800917 (2014), 26556299 (2016), 26681312 (2015), and 27433846 (2016)). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001178	SCV001158330	pathogenic	not specified	2019-04-07	criteria provided, single submitter	clinical testing	The RAD51C c.93delG; p.Phe32fs variant (rs730881942) is reported in the literature in individuals with breast and/or ovarian cancer, prostate cancer, soft tissue sarcoma, or hematologic cancer (Pelttari 2011, Pritchard 2016, Schrader 2016, Susswein 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 182847). It is found in the general population with an overall allele frequency of 0.005% (13/282860 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Pelttari LM et al. RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet. 2011 Aug 15;20(16):3278-88. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Schrader KA et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016 Jan;2(1):104-11. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32.
Sema4, Sema4	RCV000160936	SCV002530035	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000024266	SCV004019948	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.
Baylor Genetics	RCV000024266	SCV004207914	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-11-26	criteria provided, single submitter	clinical testing
OMIM	RCV000024266	SCV000045557	risk factor	Breast-ovarian cancer, familial, susceptibility to, 3	2011-08-15	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV001195009	SCV001365242	pathogenic	Ovarian neoplasm	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.
BRCAlab, Lund University	RCV000024266	SCV002589007	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2022-08-26	no assertion criteria provided	clinical testing