ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.968T>G (p.Leu323Trp) (rs587782045)

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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 RCV000130508 SCV000185377 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000475164 SCV000550197 uncertain significance Fanconi anemia, complementation group O 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with tryptophan at codon 323 of the RAD51C protein (p.Leu323Trp). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and tryptophan. This variant is present in population databases (rs587782045, ExAC 0.01%). This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 141835). 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 RCV000484566 SCV000568042 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.968T>G at the cDNA level, p.Leu323Trp (L323W) at the protein level, and results in the change of a Leucine to a Tryptophan (TTG>TGG). This variant has been reported in an individual with endometrial cancer (Ring 2016). RAD51C Leu323Trp was not observed in large population cohorts (Lek 2016). This variant is located in the region of interaction with RAD51B, RAD51D, XRCC3 (Miller 2004). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation or increase of a cryptic splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether RAD51C Leu323Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130508 SCV000686411 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing

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