ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.748del (p.His250fs) (rs587780105)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212968 SCV000149729 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing This deletion of one nucleotide in RAD51D is denoted c.748delC at the cDNA level and p.His250ThrfsX2 (H250TfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAC[delC]ACAT. The deletion causes a frameshift, which changes a Histidine to a Threonine at codon 250, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. RAD51D c.748delC has been identified in at least two individuals with triple negative breast cancer, two with ovarian cancer, and two unaffected controls, one of whom reported a family history of breast and ovarian cancer (Loveday 2011, Couch 2015, Song 2015). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000115820 SCV000185265 pathogenic Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000465960 SCV000551352 pathogenic Breast-ovarian cancer, familial 4 2018-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His250Thrfs*2) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 25452441, 26261251). ClinVar contains an entry for this variant (Variation ID: 127894). Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586494 SCV000698096 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The RAD51D c.748delC (p.His250Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51D protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple HBOC patients and is absent in 120950 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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