ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.571+5G>A

gnomAD frequency: 0.00002  dbSNP: rs145779113
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195473 SCV000255190 likely pathogenic Fanconi anemia complementation group O 2024-01-18 criteria provided, single submitter clinical testing This sequence change falls in intron 3 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 may result in an absent or disrupted protein product. This variant is present in population databases (rs145779113, gnomAD 0.04%). This variant has been observed in individual(s) with breast and ovarian cancer and/or clinical features of Fanconi anemia (PMID: 21597919, 29278735, 30093976). ClinVar contains an entry for this variant (Variation ID: 216805). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 33333735; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV000195473 SCV000598657 uncertain significance Fanconi anemia complementation group O criteria provided, single submitter clinical testing
Ambry Genetics RCV000561973 SCV000663769 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-29 criteria provided, single submitter clinical testing The c.571+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 3 in the RAD51C gene. This alteration was reported in 1/273 Chinese women with familial breast cancer who previously tested BRCA1/2 negative and also reported in an individual affected with ovarian cancer (Pang Z et al. Breast Cancer Res. Treat., 2011 Oct;129:1019-20; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). Additionally, this variant has been reported in conjunction with another variant in RAD51C in an individual diagnosed with clinical features of Fanconi anemia (Jacquinet A et al. Eur J Med Genet, 2018 May;61:257-261). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies in the literature have demonstrated that this alteration results in impaired splicing (Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12:). Internal RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000561973 SCV000691251 likely pathogenic Hereditary cancer-predisposing syndrome 2023-05-11 criteria provided, single submitter clinical testing This variant causes a G>A nucleotide substitution at the +5 position of intron 3 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A mini-gene splice assay has shown that this variant results in out-of-frame skipping of exon 3 in over 90% of the transcripts (PMID: 33333735). This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with ovarian cancer (PMID: 30093976), in two individuals affected with breast cancer (PMID: 21597919; Lertwilaiwittaya et al., 2020, DOI: https://doi.org/10.21203/rs.3.rs-122156/v1), and in an individual having clinical features of Fanconi anemia (PMID: 29278735, 36909564). All of these affected individuals were of East Asian ethnicity. This variant has been identified in 7/282860 chromosomes (7/19250 East Asian 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 Likely Pathogenic.

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