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

gnomAD frequency: 0.00001  dbSNP: rs45580035

Total submissions: 35

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, susceptibility to, 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045732	SCV000073745	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3052 of the BRCA2 protein (p.Arg3052Trp). This variant is present in population databases (rs45580035, gnomAD 0.003%). This missense change has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 18451181, 19200354, 20104584, 24504028, 24728189, 25556971, 26845104). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52763). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 18607349, 23108138, 25146914). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000163027	SCV000213515	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-14	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, several functional studies have 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; Guidugli L et al. Am. J. Hum. Genet., 2018 Jan; Mesman RLS et al. Genet Med 2019 02;21(2):293-302; Richardson ME at al. Am J Hum Genet 2021 03;108(3):458-468 ). Of note, this alteration is also designated as 9382C>T in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000221843	SCV000279425	pathogenic	not provided	2023-08-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired homology directed repair activity and cell survival, and increased sensitivity to PARP inhibitors (Farrugia et al., 2008; Kuznetsov et al., 2008; Guidugli et al., 2013; Cunningham et al., 2014; Hendriks et al., 2014; Shimelis et al., 2017; Guidugli et al., 2018; Hart et al., 2019; Ikegami et al., 2020); Observed in individuals with breast or ovarian cancer and reported to segregate with disease in affected family members (Mohammadi et al., 2009; Borg et al., 2010; Capanu et al., 2011; Cunningham et al., 2014; Song et al., 2014; Li et al., 2018); Multifactorial studies suggest this variant is associated with hereditary breast and ovarian cancer (Lindor et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9382C>T; This variant is associated with the following publications: (PMID: 18607349, 19043619, 29555025, 28277317, 29176636, 21520273, 25556971, 26221963, 31565484, 30720243, 30078507, 31360874, 20513136, 25782689, 24504028, 24323938, 24728189, 23231788, 21702907, 19200354, 26026974, 20104584, 21120943, 24963051, 19563646, 23108138, 25146914, 18451181, 28199314, 28279176, 28283652, 28487467, 28724667, 25085752, 29339979, 29988080, 29922827, 30728895, 29907814, 26845104, 29446198, 30702160, 29607586, 31159747, 32444794, 34597585, 31980526, 30787465, 35273153, 31907386, 32438681, 29884136, 35264596, 35736817, 33609447, 32853339, 29884841, 31825140, 34399810, 33629534, 35711920, 12228710, 35665744, 21990134, 29394989)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000221843	SCV000296544	pathogenic	not provided	2021-08-02	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000029 (1/34578 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer, ovarian cancer and in healthy controls (PMID: 28724667 (2017), 28283652 (2017), 26845104 (2016), 26221963 (2015), 24728189 (2014), 24504028 (2014), 21520273 (2011), 19563646 (2009), 19200354 (2009)). In addition, functional studies in the published literature demonstrate that this variant is damaging to BRCA2 protein function (PMID: 29394989 (2018), 28283652 (2017), 25146914 (2014), 18607349 (2008), 18451181 (2008)) and has been classified as pathogenic in multifactorial analyses (PMID: 23108138 (2013), 20513136 (2010)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077461	SCV000328069	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163027	SCV000537644	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-02	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). Functional studies have shown that the variant protein is defective in homology-directed DNA repair and fails to complement BRCA2-deficient mouse embryonic stem cells (PMID: 18451181, 18607349, 24323938, 29394989, 35711920). This variant has been reported in over 12 individuals affected with breast or ovarian cancer and in 1 unaffected individual (PMID: 18451181, 24728189, 25682074, 26221963, 28724667, 33471991). This variant has been reported in several families affected with hereditary breast and ovarian cancer (PMID: 19200354, 25556971) and has been identified in 22 families among the CIMBA participants (PMID: 29446198). It has been shown that this variant segregates with disease with a likelihood ratio of 3.6 from 10 carrier families (PMID: 18451181). 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, susceptibility to, 2	2017-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000045732	SCV000588126	pathogenic	Hereditary breast 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, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000077461	SCV000677705	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 2	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077461	SCV000744557	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000045732	SCV000838897	pathogenic	Hereditary breast 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 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 Center for Human Genetics Tuebingen	RCV000221843	SCV001249500	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000221843	SCV001450372	pathogenic	not provided	2018-01-25	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045732	SCV002504867	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077461	SCV003932774	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	BRCA2 (p.Arg3052Trp): This sequence change results in a non-conservative amino acid change located in the OB3 domain of the encoded protein sequence. In-silico prediction show pathogenic computational verdict based on 8 pathogenic predictions from BayesDel_addAF, DANN, FATHMM-MKL, M-CAP, MVP, MutationTaster, REVEL and SIFT vs 2 benign predictions from EIGEN and PrimateAI. It has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (PMID: 20513136 and 23108138). Functional analyses of this variant are published (PMID: 18451181, 23108138, 25146914, 18607349) describing it as deleterious. ClinVar has an entry for this variant (ClinVar 52763) with 25 submissions, all described it as pathogenic, 3 stars, no conflict, and reviewed by an expert panel. Therefore, this variant was classified as pathogenic.
Baylor Genetics	RCV000585715	SCV004210477	pathogenic	Familial cancer of breast	2024-02-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803930	SCV004846128	pathogenic	BRCA2-related cancer predisposition	2024-09-03	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). Functional studies have shown that the variant protein is defective in homology-directed DNA repair and fails to complement BRCA2-deficient mouse embryonic stem cells (PMID: 18451181, 18607349, 24323938, 29394989, 35711920). This variant has been reported in over 12 individuals affected with breast or ovarian cancer and in 1 unaffected individual (PMID: 18451181, 24728189, 25682074, 26221963, 28724667, 33471991). This variant has been reported in several families affected with hereditary breast and ovarian cancer (PMID: 19200354, 25556971) and has been identified in 22 families among the CIMBA participants (PMID: 29446198). It has been shown that this variant segregates with disease with a likelihood ratio of 3.6 from 10 carrier families (PMID: 18451181). 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000077461	SCV005046009	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PS3; PP3; PP1; Expert panel
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000221843	SCV005197329	pathogenic	not provided	2024-02-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000221843	SCV005414168	pathogenic	not provided	2024-02-12	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PP4_moderate, PS3
Sharing Clinical Reports Project (SCRP)	RCV000077461	SCV000109259	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-11-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077461	SCV000147553	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 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, susceptibility to, 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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000221843	SCV001959414	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077461	SCV004243856	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing