Submissions for variant NM_058216.3(RAD51C):c.394dup (p.Thr132fs)

dbSNP: rs730881940

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160934	SCV000211641	pathogenic	not provided	2020-02-06	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal and/or family history of breast, ovarian, and other cancer (Wang 2018, Li 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26681312, 29566657, 30949688, 32068069)
Invitae	RCV000465754	SCV000550190	pathogenic	Fanconi anemia complementation group O	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr132Asnfs*23) 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 (rs754457185, gnomAD 0.05%). 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: 182845). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000569930	SCV000663765	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	The c.394dupA pathogenic mutation, located in coding exon 2 of the RAD51C gene, results from a duplication of A at nucleotide position 394, causing a translational frameshift with a predicted alternate stop codon (p.T132Nfs*23). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32) and in a cohort of Chinese individuals diagnosed with breast cancer undergoing multigene panel testing (Wang YA et al. BMC Cancer. 2018 03;18:315). 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	RCV000569930	SCV000691230	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-22	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 2 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 (PMID: 26681312, 29566657). This variant has been identified in 10/279660 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.
Sema4, Sema4	RCV000569930	SCV002531813	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492641	SCV002779615	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2022-01-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467271	SCV004209770	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358597	SCV001554383	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Thr132AsnfsX23 variant was not identified in the literature nor was it identified in the Cosmic or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs730881940) as “With Pathogenic allele”, in ClinVar (classified as pathogenic by GeneDx, Invitae, Ambry Genetics and Color Genomics). 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 c.394dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 132 and leads to a premature stop codon at position 154. 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.