Submissions for variant NM_058216.3(RAD51C):c.404+3A>G

dbSNP: rs1060502598

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000462951	SCV000550218	uncertain significance	Fanconi anemia complementation group O	2021-11-11	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 409857). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the RAD51C gene. It does not directly change the encoded amino acid sequence of the RAD51C protein. It affects a nucleotide within the consensus splice site.
GeneDx	RCV000478818	SCV000567788	uncertain significance	not provided	2015-09-01	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.404+3A>G or IVS2+3A>G and consists of a A>G nucleotide substitution at the +3 position of intron 2 of the RAD51C gene. Multiple in silico models predict this variant to destroy the nearby natural donor site for intron 2, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C c.404+3A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is conserved across species. Based on currently available information, it is unclear whether RAD51C c.404+3A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478818	SCV001470082	uncertain significance	not provided	2020-07-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002323729	SCV002630115	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-11	criteria provided, single submitter	clinical testing	The c.404+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 2 in the RAD51C gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.