ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.404G>C (p.Cys135Ser) (rs767796996)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478459 SCV000565458 likely pathogenic not provided 2018-04-10 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.404G>C at the cDNA level. Located in the last nucleotide of exon 2, it is predicted to destroy the natural splice donor site and to cause abnormal splicing. This variant has been identified in two families with a significant history of breast and/or ovarian cancer (Neidhardt 2017). Consistent with splicing models, RT-PCR studies performed on RNA derived from probands in these families demonstrated that this variant results in aberrant splicing, ultimately leading to a prematurely truncated transcript (Neidhardt 2016). RAD51C c.404G>C was not observed in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 404, is conserved across species. Based on the current evidence, we consider RAD51C c.404G>C to be a likely pathogenic variant.
Ambry Genetics RCV000566450 SCV000671879 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Functionally-validated splicing mutation,Well-characterized mutation at same position
Invitae RCV000576215 SCV000676959 likely pathogenic Fanconi anemia, complementation group O 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 135 of the RAD51C protein (p.Cys135Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant also falls at the last nucleotide of exon 2 of the RAD51C coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with breast cancer (PMID: 27622768) and an individual with ovarian cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 418441). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant affects normal splicing, leading to the inclusion of a premature stop codon in intron 2 (PMID: 27622768). A different substitution at the same nucleotide (c.404G>T) has been shown to have the same splicing defect (PMID: 27622768), suggesting that this nucleotide is important for normal RNA splicing. In summary, this variant is a rare missense change at the consensus splice site that has been shown to affect splicing, and has been observed in affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV000566450 SCV000691235 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing

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