ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.790G>A (p.Gly264Ser) (rs147241704)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000194252 SCV000150089 likely benign not specified 2018-03-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000989962 SCV000166701 benign Fanconi anemia, complementation group O 2019-12-31 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 Insufficient or conflicting evidence;Conflicting evidence;In silico models in agreement (benign);Subpopulation frequency in support of benign classification;No disease association in small case-control study
Genetic Services Laboratory,University of Chicago RCV000194252 SCV000248653 uncertain significance not specified 2015-07-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487827 SCV000575117 uncertain significance not provided 2020-05-01 criteria provided, single submitter clinical testing
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 RCV000487827 SCV000602148 likely benign not provided 2018-08-13 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000515761 SCV000611878 likely benign Breast-ovarian cancer, familial 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 RCV000116180 SCV000691268 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 3; Fanconi anemia, complementation group O 2017-06-29 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000487827 SCV000807180 uncertain significance not provided 2016-01-20 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 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000989962 SCV001140722 uncertain significance Fanconi anemia, complementation group O 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000194252 SCV001158025 likely benign not specified 2018-07-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000515761 SCV001282872 uncertain significance Breast-ovarian cancer, familial 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.
True Health Diagnostics RCV000116180 SCV000788201 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-21 no assertion criteria provided clinical testing

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