Submissions for variant NM_058216.3(RAD51C):c.498del (p.Asp167fs)

dbSNP: rs746993675

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573580	SCV000664925	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-31	criteria provided, single submitter	clinical testing	The c.498delT pathogenic mutation, located in coding exon 3 of the RAD51C gene, results from a deletion of one nucleotide at nucleotide position 498, causing a translational frameshift with a predicted alternate stop codon (p.D167Ifs*4). In one study, this mutation was identified in a 52-year-old female diagnosed with ovarian cancer (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). In another study, this alteration was identified in two unrelated Danish female breast cancer patients (Jønson L et al. Breast Cancer Res. Treat., 2016 Jan;155:215-22). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Color Diagnostics, LLC DBA Color Health	RCV000573580	SCV000691241	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 3 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 individuals affected with breast cancer and ovarian cancer (PMID: 26261251, 26740214). This variant has been identified in 1/251466 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268182	SCV002551131	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003507290	SCV004297490	pathogenic	Fanconi anemia complementation group O	2023-10-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp167Ilefs*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 (rs746993675, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with RAD51C-related conditions (PMID: 26261251, 26740214). ClinVar contains an entry for this variant (Variation ID: 480949). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004024465	SCV004932559	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-01-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.