ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.785C>T (p.Pro262Leu) (rs730881950)

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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 RCV000160952 SCV000215198 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Counsyl RCV000543677 SCV000785924 uncertain significance Breast-ovarian cancer, familial 4 2018-01-11 criteria provided, single submitter clinical testing
GeneDx RCV000212970 SCV000211659 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.785C>T at the cDNA level, p.Pro262Leu (P262L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has been identified in at least one ovarian cancer patient (Song 2015). RAD51D Pro262Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51D Pro262Leu occurs at a position that is conserved across species and is located within the RAD51C binding domain (Miller 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether RAD51D Pro262Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000543677 SCV000651780 uncertain significance Breast-ovarian cancer, familial 4 2018-03-01 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 262 of the RAD51D protein (p.Pro262Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 182863). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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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