ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.955C>T (p.Gln319Ter) (rs794726988)

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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 RCV000566389 SCV000671928 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724431 SCV000224913 uncertain significance not provided 2018-06-19 criteria provided, single submitter clinical testing
GeneDx RCV000724431 SCV000566849 uncertain significance not provided 2017-04-12 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.955C>T at the cDNA level and p.Gln319Ter (Q319X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG). This variant has not, to our knowledge, been reported in the literature as pathogenic or benign. RAD51D Gln319Ter results in the loss of 10 amino acids at the end of the protein. However, due to the location of the created nonsense codon in the last exon, the transcript is not expected to undergo nonsense-mediated decay and could encode a truncated protein that may retain some normal function. The deleted residues are not conserved and include a portion of the RAD51C binding domain (Miller 2004). RAD51D Gln319Ter was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Based on currently available information, we consider RAD51D Gln319Ter to be a variant of uncertain significance.
Invitae RCV000173764 SCV000287735 uncertain significance Breast-ovarian cancer, familial 4 2018-11-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the RAD51D mRNA at codon 319 (p.Gln319*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein by removing the last 10 amino acids (residues 319-328) from the full length RAD51D protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 193645). This truncation is expected to partially remove the very C-terminus of the ATPase domain of RAD51D protein (PMID: 14704354, 19327148, 21111057), which is required for interacting with RAD51C to assist in DNA repair activity (PMID: 14704354, 19327148). However, functional studies have not been performed for this particular truncation and the effect of this variant on protein function is uncertain. In summary, this is a rare nonsense change that results in a truncated protein. In the absence of supporting genetic or functional data, this variant has been classified as a Variant of Uncertain Significance

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