ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.397C>T (p.Gln133Ter) (rs387907159)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219684 SCV000274438 pathogenic Hereditary cancer-predisposing syndrome 2017-06-14 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)
Counsyl RCV000205139 SCV000489817 pathogenic Fanconi anemia, complementation group O 2016-06-08 criteria provided, single submitter clinical testing
Counsyl RCV000024264 SCV000489818 pathogenic Breast-ovarian cancer, familial 3 2016-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000483994 SCV000567793 pathogenic not provided 2018-02-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted RAD51C c.397C>T at the cDNA level and p.Gln133Ter (Q133X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals with breast and/or ovarian cancer (Loveday 2012, Thompson 2012) and is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586296 SCV000699808 pathogenic Hereditary breast and ovarian cancer syndrome 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.397C>T (p.Gln133X) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51C protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar (e.g.c.577C>T/p.Arg193Ter, c.701C>G/p.Ser234Ter). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/120836 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). This variant has been reported in multiple HBOC families (Thompson_2011, Loveday_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000205139 SCV000260887 pathogenic Fanconi anemia, complementation group O 2018-11-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln133*) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs387907159, ExAC 0.002%). This variant has been reported in families with breast and/or ovarian cancer (PMID: 21990120, 22538716). ClinVar contains an entry for this variant (Variation ID: 31556). Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000024264 SCV000045555 risk factor Breast-ovarian cancer, familial 3 2012-04-26 no assertion criteria provided literature only

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