Submissions for variant NM_058216.3(RAD51C):c.701C>G (p.Ser234Ter)

dbSNP: rs587782818

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132392	SCV000187484	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The p.S234* pathogenic mutation (also known as c.701C>G), located in coding exon 4 of the RAD51C gene, results from a C to G substitution at nucleotide position 701. This changes the amino acid from a serine to a stop codon within coding exon 4. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458376	SCV000550229	pathogenic	Fanconi anemia complementation group O	2024-04-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser234*) 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 (rs587782818, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with clinical features of RAD51C-related conditions (PMID: 32107557). ClinVar contains an entry for this variant (Variation ID: 142919). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763015	SCV000893461	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132392	SCV000905211	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 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 identified in 16/251104 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.
Baylor Genetics	RCV003467194	SCV004208035	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2022-06-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467194	SCV004931442	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 termination codon and is predicted to result in premature protein truncation.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696853	SCV005197320	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358380	SCV001554096	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Ser234X variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs587782818) as “With Pathogenic allele”, ClinVar (as pathogenic by Ambry Genetics and Invitae), and Clinvitae (2x as pathogenic) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser234X variant leads to a premature stop codon at position 234 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 in hereditary breast cancer and 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.