ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.577C>T (p.Arg193Ter) (rs200293302)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129056 SCV000183755 pathogenic Hereditary cancer-predisposing syndrome 2017-10-26 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)
Color RCV000129056 SCV000292164 pathogenic Hereditary cancer-predisposing syndrome 2015-02-18 criteria provided, single submitter clinical testing
Counsyl RCV000576579 SCV000677771 pathogenic Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2017-02-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000576579 SCV000893460 pathogenic Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000212943 SCV000211615 pathogenic not provided 2019-01-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted RAD51C c.577C>T at the cDNA level and p.Arg193Ter (R193X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), 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 multiple individuals with a personal and/or family history of breast and/or ovarian cancer and is considered pathogenic (Loveday 2012, Coulet 2013, Blanco 2014, Norquist 2015, Song 2015, Tung 2016, Jian 2017).
Illumina Clinical Services Laboratory,Illumina RCV000778126 SCV000914251 pathogenic RAD51C-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing The RAD51C c.577C>T (p.Arg193Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg193Ter variant has been reported in at least five studies in which it is found in a heterozygous state in seven individuals diagnosed with ovarian cancer, two of whom are related (Loveday et al. 2012; Coulet et al. 2013; Blanco et al. 2014; Song et al. 2015; Jonson et al. 2016). The p.Arg193Ter variant was also reported in a heterozygous state in two unaffected individuals who may yet be too young to develop disease (one individual was 25 years old and the other is of unknown age). All of these individuals have a family history of breast and/or ovarian cancer and are negative for variants in the BRCA1 and BRCA2 genes. The p.Arg193Ter variant was absent from 3,928 controls and is reported at a frequency of 0.00012 in the Latino population of the Genome Aggregation Database. Although the p.Arg193Ter variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of disease penetrance and prevalence estimates. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg193Ter variant is classified as pathogenic for RAD51C-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000590531 SCV000699816 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-14 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.577C>T (p.Arg193X) 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. This variant was found in 5/120882 control chromosomes at a frequency of 0.0000414, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). Multiple publications have cited the variant in affected individuals, including a family that the variant cosegregated with disease (Blanco_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000203684 SCV000260761 pathogenic Fanconi anemia, complementation group O 2018-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg193*) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs200293302, ExAC 0.02%). This variant has been observed in individuals affected with breast cancer and ovarian cancer (PMID: 22538716, 22725699, 26261251, 25086635, 26740214). ClinVar contains an entry for this variant (Variation ID: 140849). 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.

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