ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.904+5G>T (rs587782702)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132144 SCV000187215 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Other data supporting pathogenic classification,Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000132144 SCV000691285 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing
GeneDx RCV000484863 SCV000566207 likely pathogenic not provided 2018-01-23 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.904+5G>T or IVS6+5G>T and consists of a G>T nucleotide substitution at the +5 position of intron 6 of the RAD51C gene. Multiple in silico models predict this variant to destroy the nearby natural donor site, and functional analyses, including an RT-PCR assay and a minigene assay, demonstrated that this variant causes skipping of exon 6 (Meindl 2010). This variant has been observed in several individuals with breast and/or ovarian cancer, and analysis of breast and ovarian tumor tissue in two carriers of this variant showed loss of the wild type allele, supporting a pathogenic role (Meindl 2010, Loveday 2012). The guanine (G) nucleotide that is altered is important for splicing and is conserved across species. Based on the currently available evidence, we consider RAD51C c.904+5G>T to be a likely pathogenic variant.
GeneKor MSA RCV000484863 SCV000821778 likely pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000225845 SCV000291252 likely pathogenic Fanconi anemia, complementation group O 2018-12-16 criteria provided, single submitter clinical testing This sequence change falls in intron 6 of the RAD51C gene. It does not directly change the encoded amino acid sequence of the RAD51C protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587782702, ExAC 0.002%). This variant has been reported individuals affected with breast or ovarian cancer (PMID: 22538716, 24993905), and was shown to segregate with disease in a family with breast and ovarian cancer (PMID: 20400964). ClinVar contains an entry for this variant (Variation ID: 142762). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts splicing and leads to the deletion of the exon 6 coding sequence from the RAD51C mRNA. This is predicted to result in a frameshift and premature stop codon (PMID: 20400964). 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.
OMIM RCV000007225 SCV000027421 risk factor Breast-ovarian cancer, familial 3 2010-05-01 no assertion criteria provided literature only

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