ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.93del (p.Phe32fs) (rs730881942)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000160936 SCV000215256 pathogenic Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000205375 SCV000259467 pathogenic Fanconi anemia, complementation group O 2019-12-16 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.
Counsyl RCV000576723 SCV000677786 pathogenic Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2017-06-02 criteria provided, single submitter clinical testing
Color RCV000160936 SCV000691291 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212931 SCV001134795 pathogenic not provided 2019-06-13 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001178 SCV001158330 pathogenic not specified 2019-04-07 criteria provided, single submitter clinical testing The RAD51C c.93delG; p.Phe32fs variant (rs730881942) is reported in the literature in individuals with breast and/or ovarian cancer, prostate cancer, soft tissue sarcoma, or hematologic cancer (Pelttari 2011, Pritchard 2016, Schrader 2016, Susswein 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 182847). It is found in the general population with an overall allele frequency of 0.005% (13/282860 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Pelttari LM et al. RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet. 2011 Aug 15;20(16):3278-88. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Schrader KA et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016 Jan;2(1):104-11. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32.
OMIM RCV000024266 SCV000045557 risk factor Breast-ovarian cancer, familial 3 2011-08-15 no assertion criteria provided literature only
Leiden Open Variation Database RCV001195009 SCV001365242 pathogenic Neoplasm of ovary 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.

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