ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9154C>T (p.Arg3052Trp) (rs45580035)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163027 SCV000213515 pathogenic Hereditary cancer-predisposing syndrome 2017-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA2) RCV000077461 SCV000147553 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770736 SCV000902218 pathogenic Breast and/or ovarian cancer 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000163027 SCV000537644 pathogenic Hereditary cancer-predisposing syndrome 2015-07-28 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077461 SCV000328069 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077461 SCV000677705 pathogenic Breast-ovarian cancer, familial 2 2017-04-10 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077461 SCV000744557 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000077461 SCV000605661 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000045732 SCV000588126 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077461 SCV000733333 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077461 SCV000244491 pathogenic Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
GeneDx RCV000221843 SCV000279425 pathogenic not provided 2018-10-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9154C>T at the cDNA level, p.Arg3052Trp (R3052W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). Using alternate nomenclature, this variant has been previously published as BRCA2 9382C>T. This variant has been observed in individuals with breast or ovarian cancer and reported to segregate with disease in affected family members (Mohammadi 2009, Capanu 2011, Cunningham 2014, Song 2014). Functional assays interrogating homology directed repair and cell survival demonstrated a pathogenic effect, whereas centriole amplification did not differ from wild-type (Kuznetsov 2008, Farrugia 2008, Guidugli 2013, Cunningham 2014, Hendriks 2014, Shimelis 2017, Guidugli 2018). BRCA2 Arg3052Trp was strongly predicted by Lindor et al. (2012) to be pathogenic based on a multifactorial likelihood analysis incorporating tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. BRCA2 Arg3052Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Arg3052Trp is located in the DNA binding domain (Yang 2002). Although in-silico analysis, which includes protein predictors and evolutionary conservation, suggests that this variant does not alter protein structure/function, published evidence support that this variant is deleterious. Based on currently available evidence, we consider this variant to be pathogenic.
GeneKor MSA RCV000585715 SCV000693592 pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
Genologica Medica RCV000077461 SCV000577975 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077461 SCV000743360 pathogenic Breast-ovarian cancer, familial 2 2014-10-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045732 SCV000918902 pathogenic Hereditary breast and ovarian cancer syndrome 2017-09-11 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9154C>T (p.Arg3052Trp) variant located in the Nucleic acid-binding, OB-fold domain (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. These predictions are supported by multiple functional studies (Farrugia_2008, Kuznetsov_2008, and Walker_2010) that implicate the variant to affect proper BRCA2 protein function. This variant was found in 3/246052 control chromosomes from gnomAD database at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in several patients/families with breast and/or ovarian cancer, including an evidence of cosegregation with disease in a large multi-generation family (Farrugia_2008). In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000045732 SCV000073745 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 3052 of the BRCA2 protein (p.Arg3052Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs45580035, ExAC 0.006%). This variant has been reported in individuals affected with breast, ovarian, and prostate cancer (PMID: 24728189, 24504028, 25556971, 20104584, 26845104) and it co-segregated with BRCA2-related disease in several families (PMID: 18451181, 19200354). ClinVar contains an entry for this variant (Variation ID: 52763). This variant disrputs DNA repair activity of the encoded protein product in vitro (PMID: 18451181, 23108138) and fails to rescue lethality in mouse embryonic stem cells lacking BRCA2 (PMID: 25146914, 18607349). Analyses from several statistical modeling algorithms using genetic and functional data have concluded that this variant has a high probability of causing disease (PMID: 21990134, 23108138). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000045732 SCV000838897 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221843 SCV000296544 pathogenic not provided 2016-04-12 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045732 SCV000587990 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077461 SCV000109259 pathogenic Breast-ovarian cancer, familial 2 2012-11-28 no assertion criteria provided clinical testing
True Health Diagnostics RCV000163027 SCV000787960 pathogenic Hereditary cancer-predisposing syndrome 2017-11-10 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210144 SCV000266050 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing

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