ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.224dup (p.Tyr75Ter) (rs730881939)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000258982 SCV000211640 pathogenic not provided 2018-12-13 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted RAD51C c.224dupA at the cDNA level and p.Tyr75Ter (Y75X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is AGAT[dupA]TGCT. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. RAD51C c.224dupA, also reported as c.223_224insA or c.224_225insA, has been observed in individuals with breast or ovarian cancer, with studied tumors demonstrating loss of heterozygosity (Meindl 2010, Walsh 2011, Villalona-Calero 2016, Wolf 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000160933 SCV000216856 pathogenic Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000206050 SCV000260045 pathogenic Fanconi anemia, complementation group O 2019-11-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr75*) in the RAD51C 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 reported in individuals affected with breast and ovarian cancer (PMID: 20400964, 26848151, 22006311, 26681312). This variant is also referred to as c.224insA, c.223_224insA, and 224_225insA in the literature. ClinVar contains an entry for this variant (Variation ID: 182844). 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.
Counsyl RCV000206050 SCV000490109 pathogenic Fanconi anemia, complementation group O 2016-11-14 criteria provided, single submitter clinical testing
Counsyl RCV000409268 SCV000490110 pathogenic Breast-ovarian cancer, familial 3 2016-11-14 criteria provided, single submitter clinical testing
Color RCV000160933 SCV000686334 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781788 SCV000920115 pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-09 criteria provided, single submitter clinical testing Variant summary: RAD51C c.224dupA (p.Tyr75X) 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 (e.g., p.Gln133X and p.Arg193X). The variant was absent in 246238 control chromosomes. c.224dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is likely to be associated with disease. 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 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000258982 SCV001247510 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785446 SCV000924018 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Leiden Open Variation Database RCV000258982 SCV001365250 pathogenic not provided 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitters to LOVD: Christine Rappaport, Johan den Dunnen.

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