ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.790G>A (p.Gly264Ser)

gnomAD frequency: 0.00207  dbSNP: rs147241704
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Total submissions: 32
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487827 SCV000150089 benign not provided 2020-03-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26406419, 24800917, 27978560, 27443514, 25980754, 26740214, 20400964, 22167183, 21750962, 22538716, 22725699, 22370629, 24315737, 21616938, 24993905, 25470109, 25318351, 24504028, 21990120, 27153395, 27621404, 27878467, 26976419, 26261251, 21537932, 27622768, 28829762, 29458332, 28678401, 23117857, 30374176, 26483394, 30309722, 31159747)
Invitae RCV000989962 SCV000166701 benign Fanconi anemia complementation group O 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000116180 SCV000183856 likely benign Hereditary cancer-predisposing syndrome 2019-02-12 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago RCV000194252 SCV000248653 likely benign not specified 2021-10-08 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000487827 SCV000575117 likely benign not provided 2023-05-01 criteria provided, single submitter clinical testing RAD51C: BS1
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000116180 SCV000576451 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000194252 SCV000602148 benign not specified 2021-01-06 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000515761 SCV000611878 likely benign Breast-ovarian cancer, familial, susceptibility to, 3 2018-05-09 criteria provided, single submitter research The RAD51C variant designated as NM_058216.2: c.790G>A (p.G264S) is classified as likely benign. Cosegregation analysis of two observed families was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303). The results are a combined likelihood ratio of 1.553 (Thompson, et al., 2003, PMID:2900794), which provides supporting evidence that the variant is pathogenic. However, this variant has been reported to be present in approximately 1 in every 161 individuals with European ancestry and South Asian ancestry (exac.broadinstitute.org), which is more common than known ovarian cancer risk variants. This population frequency is not consistent with a high-risk cancer variant and supports a classification of likely benign. Additionally, this variant has been reported in multiple families with breast and ovarian cancer who also tested positive for known pathogenic mutations in BRCA1 and BRCA2. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter RAD51C function or modify cancer risk for breast and ovarian cancer. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This variant is not predicted to alter EPCAM function or modify risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Diagnostics, LLC DBA Color Health RCV000116180 SCV000691268 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000487827 SCV000699826 benign not provided 2017-04-20 criteria provided, single submitter clinical testing Variant summary: The c.790G>A (p.Gly264Ser) in RAD51C gene is a missense change that involves a conserved nucleotide. The variant is located within the conserved domain Rad51_DMC1_radA, but is located outside of multimer (BRC) interface. 3/4 in silico tools predict deleterious outcome and in functional studies the variant displayed hypomorphic effects with partial repair function and partially defective homologous recombination activity.(Meindl, 2010; Somyajit, 2012; Somyajit, 2015). The variant is present in the large control population dataset of ExAC and gnomAD at a similar frequencies of 0.001853 (225/121398 and 483/277178 chrs tested, respectively), predominantly in individuals of European descent (0.003410; 207/66736 and 432/126686 chrs tested), including 2 homozygotes. These frequencies exceed the maximal expected frequency of a pathogenic allele (0.0000625) in this gene. However, this variant has been cited in breast and ovarian cancer patients at greater frequency than in controls, and several publications indicate that this variant is an ovarian cancer risk allele (Song et al 2015, Loveday at al 2012, Meindl et al 2010). The odd's ratios calculated for its association with cancer across multiple independent studies have been in the range of 1.9-4, with the 95% CI including 1.0, example, OR 1.93 across all breast cancer cases with a CI of 0.5-7.46 as reported by Pelttari et al (2011). According to the ACMG guidelines if the CI includes 1.0, there is little confidence in the assertion of association. The guidelines state that studies with OR>5.0 and where the 95% CI does not include 1.0 are considered as strong evidence in favor of pathogenicity. The variant has been reported in probands from multiple HBOC families, including 3 families tested positive for disease-causing mutation in BRCA1 (p.Tyr1463Ter), BRCA2 (c.8632+1G>T) or BRCA2 (p.Lys944Ter), respectively. The variant was also identified in one internal LCA specimen in co-occurrence with a known pathogenic variant in CHEK2 (c.1100delC). Lastly, several reputable databases/clinical laboratories cite the variant with classification of Benign/Likely Benign. Taking all line of evidence into consideration, the variant was conservatively classified as Benign.
Counsyl RCV000662625 SCV000785292 likely benign Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O 2017-06-29 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV000194252 SCV000807180 likely benign not specified 2020-09-15 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116180 SCV000821805 likely benign Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000709513 SCV000839337 benign Hereditary breast ovarian cancer syndrome 2023-08-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000487827 SCV001158025 likely benign not provided 2023-09-12 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000989962 SCV001281690 uncertain significance Fanconi anemia complementation group O 2017-12-18 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV000515761 SCV001282872 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 3 2017-12-18 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000487827 SCV002010572 likely benign not provided 2021-11-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798366 SCV002043694 likely benign Breast and/or ovarian cancer 2023-06-29 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000116180 SCV002530018 benign Hereditary cancer-predisposing syndrome 2020-07-28 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000194252 SCV002551140 likely benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV002272129 SCV002556980 uncertain significance Familial cancer of breast 2022-06-17 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000515761 SCV004017738 likely benign Breast-ovarian cancer, familial, susceptibility to, 3 2023-04-06 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
True Health Diagnostics RCV000116180 SCV000788201 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-21 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001270343 SCV001450567 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The RAD51C p.Gly264Ser variant was identified in 95 of 24,640 proband chromosomes (frequency: 0.004) from individuals or families with endometrial, pancreatic, colorectal, breast or ovarian cancer and was present in 40 of 16846 control chromosomes (frequency: 0.002) from healthy individuals (Meindl 2009, Vuorela 2011, Thompson 2012, Schekenbach 2014, Song 2015, Leeneer 2012, Loveday 2012, Coulet 2013, Cunningham 2014, Gevensleben 2014, Hu 2016, Jonson 2015 26740214, Ring 2016, Pearlman 2017). The variant was also identified in dbSNP (rs147241704) as 'Auwith other allele'Au, ClinVar (classified as uncertain significance by PreventionGenetics and 7 other submitters; as likely benign by Ambry Genetics, GeneDx, Counsyl and 4 other submitters; and as benign by Color, Invitae and Integrated Genetics) and LOVD 3.0 (observed 14x). The variant was identified in control databases in 459 of 268,284 chromosomes (2 homozygous) at a frequency of 0.002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 404 of 118,138 chromosomes (freq: 0.003, increasing the likelihood that this is a low frequency benign variant), Other in 13 of 6704 chromosomes (freq: 0.002), Finnish in 19 of 25,102 chromosomes (freq: 0.0008), African in 14 of 23,600 chromosomes (freq: 0.0006), Ashkenazi Jewish in 3 of 9860 chromosomes (freq: 0.0003), South Asian in 4 of 30,522 chromosomes (freq: 0.0001), and Latino in 2 of 35,106 chromosomes (freq: 0.00006); it was not observed in the East Asian population. The Gly264Ser variant showed some evidence of association with malignancies in the subgroup of hereditary breast and ovarian cancer families (odds ratio=3.44, confidence interval=1.51'Ai7.80, p=5.32*10'Ai3; Meindl 2009). In addition, expression of the variant only partially restored the MMC sensitivity of RAD51C DT40 cells compared to the wild-type cDNA, suggesting the possibility of a hypomorphic mutation with reduced protein activity (Meindl 2009, Somyajit 2012). However, this variant has been identified in multiple cases with co-occurring, pathogenic variants (BRCA1 p.Tyr1463*, BRCA2 c.8632+1G>T, and BRCA2 p.Lys944*; Integrated Genetics internal data per ClinVar submission dated 25 Jan 2018); this decreases the likelihood that this RAD51C variant has clinical significance. The p.Gly264 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000487827 SCV001809164 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000487827 SCV001906291 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000487827 SCV001958992 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000487827 SCV001976142 likely benign not provided no assertion criteria provided clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000709513 SCV001977056 uncertain significance Hereditary breast ovarian cancer syndrome 2021-09-27 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000487827 SCV002036297 likely benign not provided no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000487827 SCV002074578 not provided not provided no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 08-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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