ClinVar Miner

Submissions for variant NM_058216.2(RAD51C):c.93delG (p.Phe32Serfs) (rs730881942)

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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 RCV000160936 SCV000215256 pathogenic Hereditary cancer-predisposing syndrome 2018-03-09 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 RCV000160936 SCV000691291 pathogenic Hereditary cancer-predisposing syndrome 2014-12-18 criteria provided, single submitter clinical testing
Counsyl RCV000576723 SCV000677786 pathogenic Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2017-06-02 criteria provided, single submitter clinical testing
GeneDx RCV000212931 SCV000211643 pathogenic not provided 2019-01-10 criteria provided, single submitter clinical testing This deletion of one nucleotide in RAD51C is denoted c.93delG at the cDNA level and p.Phe32SerfsX8 (F32SfsX8) at the protein level. The normal sequence, with the base that is deleted in brackets, is CGGG[delG]TTCC. The deletion causes a frameshift, which changes a Phenylalanine to a Serine at codon 32, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. RAD51C c.93delG has been reported in several families with breast and/or ovarian cancer, in at least one individual with prostate cancer, and has been described as a Finnish founder pathogenic variant (Pelttari 2011, Pritchard 2016). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587817 SCV000699829 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-22 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.93delG (p.Phe32SerfsX8) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 15/250416 control chromosomes at a frequency of 0.0000599, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). This variant has also been reported in multiple families and individuals with breast and/or ovarian cancer and based on haplotype analysis authors concluded that it is likely a founder mutation in the Finnish population that is associated with moderate-to-high risk susceptibility for ovarian cancer (Pelttari 2011). The founder effect can also explain the higher occurrence of the variant in this population (gnomAD 5/22298 Finnish European). The variant was also found in a patient with ovarian cancer in a different population (Susswein 2016). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.97C>T (p.Gln33X), c.397C>T (p.Gln133X), c.577C>T (p.Arg193X)). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000205375 SCV000259467 pathogenic Fanconi anemia, complementation group O 2018-04-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe32Serfs*8) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs763897044, ExAC 0.02%). This variant has been reported in multiple individuals and families with breast and/or ovarian cancer (PMID: 21616938), and an individual with prostate cancer (PMID: 27433846). This variant has been reported as a putative founder mutation for breast and/or ovarian cancer risk in individual of Finnish ancestry (PMID: 21616938, 24800917). ClinVar contains an entry for this variant (Variation ID: 182847). 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 RCV000024266 SCV000045557 risk factor Breast-ovarian cancer, familial 3 2011-08-15 no assertion criteria provided literature only

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