ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.458G>A (p.Gly153Asp) (rs765730332)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164871 SCV000215556 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Deficient protein function in appropriate functional assay(s)
Color RCV000164871 SCV000909443 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-04 criteria provided, single submitter clinical testing
GeneDx RCV000587056 SCV000293455 uncertain significance not provided 2016-02-05 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.458G>A at the cDNA level, p.Gly153Asp (G153D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant was observed in an individual with breast and ovarian cancer, and functional study demonstrated loss of interaction with XRCC3 and RAD51B (Clague 2011). RAD51C Gly153Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Gly153Asp occurs at a position that is conserved across species and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider RAD51C Gly153Asp to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587056 SCV000699811 uncertain significance not provided 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The c.458G>A (p.Gly153Asp) in RAD51C gene is a missense change that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is located outside of any known functional domain. Yet, functional studies have shown that this missense change alters the ability of RAD51C protein to form a complex with XRCC1 and RAD51B. (Clague, 2011). The variant is present in the large control population dataset of ExAC at a low frequency 0.000008 (1/121372 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.00006) in this gene. The variant has been reported in at least 1 affected individuals in the literature without segregation analysis being performed. In addition, several reputable databases/clinical laboratories classify the variant as VUS. Lastly, this variant was identified in an internal specimen undergoing genetic testing together with c.1100delC in CHEK2 gene. Taken together, the variant was classified as VUS until more data become available.
Invitae RCV000226827 SCV000291229 uncertain significance Fanconi anemia, complementation group O 2018-04-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 153 of the RAD51C protein (p.Gly153Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (ExAC <0.01%). This variant has been reported in two affected members of a family with hereditary breast and ovarian cancer (PMID: 21980511). ClinVar has an entry for this variant (Variation ID: 185444). Experimental studies have shown that this missense change alters the ability of the RAD51C protein to form a complex with XRCC1 and RAD51B (PMID: 21980511). 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 RCV000587056 SCV000807171 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing

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