Submissions for variant NM_058216.3(RAD51C):c.68_72dup (p.Val25fs)

dbSNP: rs2047807048

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036160	SCV001199511	pathogenic	Fanconi anemia complementation group O	2022-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val25Cysfs*3) 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). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 835311). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 21990120).
Myriad Genetics, Inc.	RCV004030972	SCV004931687	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.
Baylor Genetics	RCV004030972	SCV005052673	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-03-29	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001195008	SCV001365240	pathogenic	Ovarian neoplasm	2011-08-25	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358167	SCV001553837	pathogenic	not provided		no assertion criteria provided	clinical testing	The RAD51C p.Val25Cysfs*3 variant was identified in 1 of 2776 proband chromosomes (frequency: 0.0004) from individuals or families with ovarian cancer and was not identified in 854 control chromosomes from healthy individuals (Thompson 2012). The variant was also identified in LOVD 3.0 (1x). The variant was not identified in dbSNP, ClinVar, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict that this variant may create a new 5’ splice site which could disrupt the protein and lead to loss of function. However, this information is not predictive enough to assume pathogenicity. The c.68_72dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 25 and leads to a premature stop codon at codon 27. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the RAD51C gene are an established mechanism of disease in RAD51C associated cancers 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.