ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9154C>T (p.Arg3052Trp) (rs45580035)

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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Invitae RCV000045732 SCV000073745 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-24 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.
Ambry Genetics RCV000163027 SCV000213515 pathogenic Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing The p.R3052W pathogenic mutation (also known as c.9154C>T), located in coding exon 23 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9154. The arginine at codon 3052 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in numerous families and individuals with breast and/or ovarian cancer (Gómez García EB et al. Breast Cancer Res. 2009; 11(1):R8; Cunningham JM, Sci Rep 2014; 4:4026; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119). This alteration has been classified as pathogenic or likely pathogenic by several studies utilizing the following line(s) of evidence: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and/or functional assay results (Karchin R et al. Cancer Inform, 2008 Apr;6:203-16; Mohammadi L et al. BMC Cancer, 2009 Jun;9:211; Capanu M et al. Genet. Epidemiol., 2011 Jul;35:389-97; Lindor NM et al. Hum Mutat. 2012 Jan; 33(1):8-21). Additionally, two functional studies using mouse embryonic stem cells and bacterial artificial chromosomes found this alteration to be pathogenic (Kuznetsov SG et al. Nat. Med., 2008 Aug;14:875-81; Hendriks G et al. Hum. Mutat., 2014 Nov;35:1382-91), and a homology-directed DNA break repair assay indicated that this alteration has over 99% probability of pathogenicity (Guidugli L et al. Am. J. Hum. Genet., 2018 Jan). Of note, this alteration is also designated as 9382C>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221843 SCV000296544 pathogenic not provided 2016-04-12 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
Color Health, Inc RCV000163027 SCV000537644 pathogenic Hereditary cancer-predisposing syndrome 2021-02-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 3052 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have found this variant protein to be defective in homology-directed DNA repair, complementation of BRCA2-deficient mouse embryonic stem cells and other anxillary assays (PMID: 18451181, 18607349, 24323938, 25146914, 29394989). This variant has been observed in individuals and families affected with breast and/or ovarian cancer (PMID: 18451181, 19200354, 24504028, 24728189, 25556971, 25682074, 26221963, 28724667) and found to cosegregate with disease with likelihood ratio of 3.6 from 10 carrier families (PMID: 18451181). This variant also has been reported in an individual affected with melanoma and kidney and prostate cancer (PMID: 26845104). This variant has been identified in 3/251190 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Genologica Medica RCV000077461 SCV000577975 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 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
Department of Medical Genetics, Oslo University Hospital RCV000077461 SCV000605661 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Counsyl RCV000077461 SCV000677705 pathogenic Breast-ovarian cancer, familial 2 2017-04-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000585715 SCV000693592 pathogenic Familial cancer of breast 2020-01-01 criteria provided, single submitter clinical testing This is a single base substitution replacing Arginine with Tryptophan at codon 3052 of the BRCA2 protein. The arginine residue is highly conserved and there is a large physicochemical difference between arginine and tryptophan (Grantham Score 101). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. This variant has been described in the international literature in patients affected with breast cancer (PMID: 18451181, PMID: 19200354 , BMC Cancer. 2009, 9:211; PMID: 21520273, PMID: 24504028). Experimental studies have shown that this missense change results in the loss of DNA repair activity of the encoded protein product in vitro (PMID: 18451181,PMID: 18607349). The mutation database ClinVar contains entries for this variant (Variation ID: 52763).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077461 SCV000743360 pathogenic Breast-ovarian cancer, familial 2 2014-10-08 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
Mendelics RCV000045732 SCV000838897 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045732 SCV000918902 pathogenic Hereditary breast and ovarian cancer syndrome 2021-01-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9154C>T (p.Arg3052Trp) results in a non-conservative amino acid change located in the OB3 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251190 control chromosomes. c.9154C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Farrugia_2008, GomezGarcia_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Farrugia_2008, Kuznetsov_2008, Walker_2010). Ninteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000221843 SCV001249500 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000221843 SCV001450372 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077461 SCV000109259 pathogenic Breast-ovarian cancer, familial 2 2012-11-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077461 SCV000147553 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided 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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077461 SCV000733333 pathogenic Breast-ovarian cancer, familial 2 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356308 SCV001551438 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Arg3052Trp variant was identified in 5 of 10664 proband chromosomes (frequency: 0.0005) from individuals or families with breast and ovarian cancer (Borg 2010, Cunningham 2014, Trujillano 2015, Song 2014). The variant was also identified in the following databases: dbSNP (ID: rs45580035) as "With Pathogenic allele", ClinVar (13x pathogenic, 1x uncertain significance), Clinvitae (6X pathogenic), LOVD 3.0 (reported 50x, predicted deleterious), UMD-LSDB (10 records, causal), BIC Database (8x, clinical importance unknown), and ARUP Laboratories (definitely pathogenic). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 3 of 246052 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 1 of 33572 chromosomes (freq: 0.00003), European in 1 of 111550 chromosomes (freq: 0.000009), and South Asian in 1 of 30782 chromosomes (freq: 0.00003). The variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. Functional studies investigating the DNA break repair activity of p.Arg3052Trp showed reduced activity of this variant (Farrugia 2008, Guidugli 2013). A study using mouse embryonic stem cells and bacterial artificial chromosomes demonstrated that cells expressing p.Arg3052Trp did not survive, suggesting it to be deleterious (Borg 2010). The p.Arg3052 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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 pathogenic.

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