ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.118G>A (p.Glu40Lys) (rs786204086)

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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 RCV000220378 SCV000276508 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000220378 SCV000909436 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
GeneDx RCV000482450 SCV000568001 uncertain significance not provided 2015-09-21 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.118G>A at the cDNA level, p.Glu40Lys (E40K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Glu40Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Glu40Lys occurs at a position that is conserved in mammals and is located in a region required for Holliday junction resolution activity (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether RAD51C Glu40Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000167983 SCV000218631 uncertain significance Fanconi anemia, complementation group O 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 40 of the RAD51C protein (p.Glu40Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 188123). 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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