ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.772C>T (p.Arg258Cys) (rs587782474)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131582 SCV000186592 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000131582 SCV000686386 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000662865 SCV000785750 uncertain significance Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2017-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000679803 SCV000565460 uncertain significance not provided 2016-07-13 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.772C>T at the cDNA level, p.Arg258Cys (R258C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Arg258Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Arg258Cys occurs at a position that is conserved and is within the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether RAD51C Arg258Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000460132 SCV000550232 uncertain significance Fanconi anemia, complementation group O 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 258 of the RAD51C protein (p.Arg258Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587782474, ExAC 0.006%). This variant has been reported in an individual affected with lung squamous cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 142453). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg258His) has been determined to be likely pathogenic (PMID: 20400963, 25154786, 26740214). This suggests that the arginine residue is critical for RAD51C protein function and that other missense substitutions at this position may also be pathogenic. 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.
PreventionGenetics RCV000679803 SCV000807178 uncertain significance not provided 2016-05-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484433 SCV000602144 uncertain significance not specified 2016-12-06 criteria provided, single submitter clinical testing

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