ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.97C>T (p.Gln33Ter)

gnomAD frequency: 0.00001  dbSNP: rs587782528
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131716 SCV000186754 pathogenic Hereditary cancer-predisposing syndrome 2021-07-08 criteria provided, single submitter clinical testing The p.Q33* pathogenic mutation (also known as c.97C>T), located in coding exon 1 of the RAD51C gene, results from a C to T substitution at nucleotide position 97. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This mutation has been observed in an individual with ovarian cancer and in an unaffected individual with a family history of ovarian cancer (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000212932 SCV000211638 pathogenic not provided 2023-07-06 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with ovarian cancer, acute myeloid leukemia, and breast cancer (Lu et al., 2015; Song et al., 2015; Lilyquist et al., 2018; Carter et al., 2018; Lu et al., 2019; Palmer et al., 2020); This variant is associated with the following publications: (PMID: 26681312, 26261251, 30128536, 29922827, 34887416, 26689913, 28888541, 30322717, 32427313, 29625052, 32107557, 36451132, 33804961)
Labcorp Genetics (formerly Invitae), Labcorp RCV000196217 SCV000253965 pathogenic Fanconi anemia complementation group O 2024-01-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln33*) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is present in population databases (rs587782528, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and endometrial cancer (PMID: 26261251, 26681312). ClinVar contains an entry for this variant (Variation ID: 142534). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000196217 SCV000489955 pathogenic Fanconi anemia complementation group O 2016-08-26 criteria provided, single submitter clinical testing
Counsyl RCV000410098 SCV000489956 pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2016-08-26 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131716 SCV000537681 pathogenic Hereditary cancer-predisposing syndrome 2022-11-07 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 1 of the RAD51C gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with ovarian cancer, endometrial cancer and breast cancer (PMID: 26261251, 26681312, 32107557, 32427313). This variant has been identified in 3/251468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589795 SCV000699813 pathogenic Hereditary breast ovarian cancer syndrome 2021-08-13 criteria provided, single submitter clinical testing Variant summary: RAD51C c.97C>T (p.Gln33X) 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 1.2e-05 in 257012 control chromosomes. c.97C>T has been reported in the literature in individuals affected with ovarian and endometrial cancer (Song_2015, Susswein_2016, Carter_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000410098 SCV002584615 pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2022-09-06 criteria provided, single submitter clinical testing The RAD51C c.97C>T (p.Gln33Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of the protein due to nonsense mediated decay. This variant has been identified in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 26261251, 32107557, 32427313). This variant has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120). In summary, this variant meets criteria to be classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology RCV000410098 SCV002761598 pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2020-06-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002505114 SCV002806572 pathogenic Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O 2022-03-22 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000410098 SCV004019945 pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2023-04-05 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics RCV000410098 SCV004207931 pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2023-09-27 criteria provided, single submitter clinical testing
BRCAlab, Lund University RCV000410098 SCV002589008 pathogenic Breast-ovarian cancer, familial, susceptibility to, 3 2022-08-26 no assertion criteria provided clinical testing

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