ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.859A>G (p.Thr287Ala) (rs28363317)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119137 SCV000153852 benign Fanconi anemia, complementation group O 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000212950 SCV000171268 benign not specified 2013-10-02 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.
Ambry Genetics RCV000130980 SCV000185897 benign Hereditary cancer-predisposing syndrome 2014-06-27 criteria provided, single submitter clinical testing This alteration is classified as 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000212950 SCV000297363 benign not specified 2015-07-29 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000305956 SCV000404323 likely benign Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000341847 SCV000404324 likely benign Breast and Ovarian Cancer Susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000119137 SCV000489833 likely benign Fanconi anemia, complementation group O 2016-06-13 criteria provided, single submitter clinical testing
Counsyl RCV000411553 SCV000489834 likely benign Breast-ovarian cancer, familial 3 2016-06-13 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000426921 SCV000511148 likely benign not provided 2016-10-10 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Color Health, Inc RCV000130980 SCV000537377 benign Hereditary cancer-predisposing syndrome 2020-12-10 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212950 SCV000596686 benign not specified 2017-06-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212950 SCV000602149 likely benign not specified 2017-04-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000426921 SCV000692917 likely benign not provided 2021-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000426921 SCV000699827 benign not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.859A>G (p.Thr287Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 693/126274 control chromosomes (3 homozygotes) at a frequency of 0.0054881, which is approximately 88 times the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple cancer patients (including BrC, OvC, PcC) and some studies reported comparable frequencies of variant in case and controls. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign, without evidence to independently evaluate. Complementation assays of T287A have shown that a normal number of RAD51C foci are formed. Cells survival is reduced by ~36% in chicken DT40 cells, which may not be replicated in mammalian cells or associated with the pathology of HBOC (Meindl_2010). Considering all evidence, this variant is classified as benign.
PreventionGenetics,PreventionGenetics RCV000426921 SCV000807181 likely benign not provided 2016-07-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000212950 SCV000854935 benign not specified 2018-08-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000426921 SCV000888606 benign not provided 2018-04-20 criteria provided, single submitter clinical testing
Mendelics RCV000119137 SCV001140725 benign Fanconi anemia, complementation group O 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287874 SCV001474615 benign none provided 2020-02-02 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000130980 SCV000788202 likely benign Hereditary cancer-predisposing syndrome 2018-01-05 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354676 SCV001549352 benign Malignant tumor of breast no assertion criteria provided clinical testing The RAD51C p.Thr287Ala variant was identified in 57 of 8266 proband chromosomes (frequency: 0.007) from Australian, British, German, American, Jewish and Other individuals or families with non- BRCA1/BRCA2 (high risk or familial) breast and/or ovarian cancer and was identified in 35 of 6604 control chromosomes (frequency: 0.005) from healthy individuals (Thompson 2012, Neidhardt 2017, Meindl 2009, Lu 2012, Clague 2011, Kushnir 2012, Leeneer 2012, Lu 2012). Three groups assessed RAD51C protein function for this variant, genomic stability and homologous recombination through functional assays and found that the variant is hypomorphic (Meindl 2009, Somyajit 2012, Clague 2011). However, complementation studies of this variant with a mutant RAD51C human fibroblast cell line demonstrated correction of the phenotype. The variant was also identified in dbSNP (ID: rs28363317) as “Other”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics, Children's Hospital of Philadelphia, Color Genomics; and likely benign by Illumina, Counsyl, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics), and LOVD 3.0 (9X); but was not identified in Clinvitae, Cosmic, and MutDB databases. The variant was identified in control databases in 1542 (6 homozygous) of 276966 chromosomes at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017)". The p.Thr287Ala residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000212950 SCV001809406 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000426921 SCV001906011 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000212950 SCV001953716 benign not specified no assertion criteria provided clinical testing

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