ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.548T>C (p.Ile183Thr) (rs756727559)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167442 SCV000218298 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000204055 SCV000260317 uncertain significance Fanconi anemia, complementation group O 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 183 of the RAD51C protein (p.Ile183Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs756727559, ExAC 0.01%). This variant has been reported in an individual affected with ovarian cancer (PMID: 22538716). ClinVar contains an entry for this variant (Variation ID: 187692). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000483939 SCV000568394 uncertain significance not provided 2018-02-05 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.548T>C at the cDNA level, p.Ile183Thr (I183T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant was observed in 1/2,808 ovarian cancer cases and was absent from 2,312 controls (Loveday 2012). RAD51C Ile183Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Ile183Thr is located in the RAD51B, RAD51D, and XRCC3 interaction domain (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether RAD51C Ile183Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000167442 SCV000909446 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing

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