Submissions for variant NM_058216.3(RAD51C):c.653_654del (p.Glu218fs)

dbSNP: rs587782286

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166223	SCV000186089	pathogenic	Hereditary cancer-predisposing syndrome	2013-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000166223	SCV000217002	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	The c.653_654delAG pathogenic mutation, located in coding exon 4 of the RAD51C gene, results from a deletion of two nucleotides between nucleotide positions 653 and 654, causing a translational frameshift with a predicted alternate stop codon (p.E218Vfs*33). This alteration has been observed in multiple individuals and families with high risk breast and ovarian cancer (Song H et al. J. Clin. Oncol. 2015 Sep;33(26):2901-7; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Suszynska M et al. J Ovarian Res, 2020 May;13:50). In addition, this mutation is also designated as 651_652delAG in published literature. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000996589	SCV001151382	likely pathogenic	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385150	SCV001584910	pathogenic	Fanconi anemia complementation group O	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu218Valfs*33) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 26261251). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498821	SCV002807061	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2021-08-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462204	SCV004208046	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2022-01-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003462204	SCV004930368	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-01-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782272	SCV005394148	pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-03	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.653_654delAG (p.Glu218ValfsX33) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.653_654delAG has been reported in the literature in individuals affected with Hereditary Cancer Syndrome (LaDuca_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24763289). ClinVar contains an entry for this variant (Variation ID: 186604). Based on the evidence outlined above, the variant was classified as pathogenic.