ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205139 SCV000260887 pathogenic Fanconi anemia, complementation group O 2019-12-13 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.
Ambry Genetics RCV000219684 SCV000274438 pathogenic Hereditary cancer-predisposing syndrome 2019-01-22 criteria provided, single submitter clinical testing 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 2019-06-03 criteria provided, single submitter clinical testing Variant summary: RAD51C c.397C>T (p.Gln133X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes (gnomAD). c.397C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Hu_2018, Loveday_2012, Thompson_2011) including a family in which an unaffected individual carried the variant suggesting reduced penetrance (Thompson_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000219684 SCV001350188 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
OMIM RCV000024264 SCV000045555 risk factor Breast-ovarian cancer, familial 3 2012-04-26 no assertion criteria provided literature only
Leiden Open Variation Database RCV000483994 SCV001365256 pathogenic not provided 2011-08-25 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.

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