ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.837+1G>T (rs760235677)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226369 SCV000291249 likely pathogenic Fanconi anemia, complementation group O 2017-07-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the RAD51C gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD51C-related disease. However, a different nucleotide change at this position(c.837+1G>A) has been reported in an individual with ovarian cancer (PMID: 21616938) ClinVar contains an entry for this variant (Variation ID: 241779). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917). 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.
Counsyl RCV000226369 SCV000489917 likely pathogenic Fanconi anemia, complementation group O 2016-08-10 criteria provided, single submitter clinical testing
Counsyl RCV000409098 SCV000489918 likely pathogenic Breast-ovarian cancer, familial 3 2016-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000481912 SCV000570749 likely pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.837+1G>T or IVS5+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 5 of the RAD51C gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Although this exact variant has not been reported in the literature, the G>A change at the same position was seen in several breast and ovarian cancer families, with RT-PCR analysis of two probands revealing two aberrant transcripts, one leading to an in frame deletion of exon 5 and the other leading to an out of frame deletion of exons 4 and 5, resulting in premature truncation (Pelttari 2011). Based on the currently available information, we consider RAD51C c.837+1G>T to be a likely pathogenic variant.

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