Submissions for variant NM_058216.3(RAD51C):c.561_562del (p.His187fs)

dbSNP: rs1057517812

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413272	SCV000490760	likely pathogenic	not provided	2017-09-06	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in RAD51C is denoted c.561_562delCA at the cDNA level and p.His187GlnfsX15 (H187QfsX15) at the protein level. The normal sequence, with the bases that are deleted in braces, is AACA[CA]AGGG. The deletion causes a frameshift which changes a Histidine to a Glutamine at codon 187, and creates a premature stop codon at position 15 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208604	SCV001380002	pathogenic	Fanconi anemia complementation group O	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His187Glnfs*15) 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 variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 372486). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002348128	SCV002649211	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-28	criteria provided, single submitter	clinical testing	The c.561_562delCA pathogenic mutation, located in coding exon 3 of the RAD51C gene, results from a deletion of two nucleotides at nucleotide positions 561 to 562, causing a translational frameshift with a predicted alternate stop codon (p.H187Qfs*15). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Myriad Genetics, Inc.	RCV004022156	SCV004932420	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000413272	SCV002034944	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413272	SCV002037327	pathogenic	not provided		no assertion criteria provided	clinical testing