Submissions for variant NM_058216.3(RAD51C):c.1027-2A>G

dbSNP: rs587780835

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123368	SCV000166691	uncertain significance	Fanconi anemia complementation group O	2023-06-04	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). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 9 (Invitae). ClinVar contains an entry for this variant (Variation ID: 136155). Disruption of this splice site has been observed in individual(s) with personal and family history of breast and/or ovarian cancer (PMID: 26270727). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 2 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Ambry Genetics	RCV001017020	SCV001178040	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-05	criteria provided, single submitter	clinical testing	The c.1027-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 9 in the RAD51C gene. This alteration has been observed in the literature in one patient with ovarian cancer (Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of two amino acids; however, the exact functional impact of the deleted amino acids are unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235048	SCV003934072	uncertain significance	not specified	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.1027-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Four predict the variant creates a cryptic 3 acceptor site and results in an in-frame deletion of two amino acids. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-06 in 294720 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1027-2A>G has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome, as well as in controls (Desmond_2015, Mizukami_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26270727, 35806449, 32980694). Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Genotyping Development, RIKEN	RCV003162564	SCV002758224	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research