ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.106G>A (p.Glu36Lys) (rs773998134)

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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 RCV000569780 SCV000667108 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000569780 SCV000911102 likely benign Hereditary cancer-predisposing syndrome 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000484571 SCV000570449 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.106G>A at the cDNA level, p.Glu36Lys (E36K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been observed in breast and/or ovarian cancer families (Romero 2011, Osorio 2012, Golmard 2013). RAD51C Glu36Lyswas not observed at a significant allele frequency in large population cohorts (Lek 2016). RAD51C Glu36Lys is located within a region required for Holliday junction resolution activity (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51C Glu36Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200867 SCV000255184 uncertain significance Fanconi anemia, complementation group O 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 36 of the RAD51C protein (p.Glu36Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs773998134, ExAC 0.003%). This variant has not been reported in the literature in individuals with RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 216803). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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