Submissions for variant NM_058216.3(RAD51C):c.837+4_837+7del

dbSNP: rs727503760

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656963	SCV000150090	likely pathogenic	not provided	2019-12-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26681312)
Ambry Genetics	RCV000116181	SCV000273797	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	The c.837+4_837+7delAGTA intronic variant, located in intron 5 of the RAD51C gene, results from a deletion of 4 nucleotides within intron 5 of the RAD51C gene. This variant has been observed in an individual affected with breast cancer (Susswein LR et al. Genet Med, 2016 08;18:823-32). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000696562	SCV000825126	pathogenic	Fanconi anemia complementation group O	2023-04-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RAD51C protein in which other variant(s) (p.Arg258His) have been determined to be pathogenic (PMID: 20400963, 22167183, 25154786, 26354865, 26740214, 32054657, 32242007). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 35740625; Invitae). ClinVar contains an entry for this variant (Variation ID: 128212). This variant has been observed in individual(s) with breast cancer (PMID: 26681312). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the RAD51C gene. It does not directly change the encoded amino acid sequence of the RAD51C protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Color Diagnostics, LLC DBA Color Health	RCV000116181	SCV004357130	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-09	criteria provided, single submitter	clinical testing	This variant causes a deletion of 4 nucleotides (c.837+4_837+7del) in intron 5 splice donor site of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A mini-gene splicing assay has shown that this variant results in in-frame skipping of exon 5 (PMID: 35740625). This variant has not been reported in individuals affected with ovarian cancer but has been reported in an individual affected with breast cancer (PMID: 26681312). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, the available functional and clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.