Submissions for variant NM_000059.4(BRCA2):c.9097dup (p.Thr3033fs)

dbSNP: rs397507419

Total submissions: 43

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031791	SCV000282467	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195406	SCV000073724	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr3033Asnfs*11) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 9150172, 21138478, 22970155, 25940717). This variant is also known as c.9097_9098insA, 9325insA and 9317insA. ClinVar contains an entry for this variant (Variation ID: 38208). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130439	SCV000185303	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-08	criteria provided, single submitter	clinical testing	The c.9097dupA pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a duplication of one nucleotide at position 9097, causing a translational frameshift with a predicted alternate stop codon (p.T3033Nfs*11). This mutation has been described in multiple breast, ovarian and/or pancreatic cancer families across multiple ethnic groups (Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May;60:1236-9; Machackova E et al. BMC Cancer. 2008 May;8:140; Kwong A et al. PLoS ONE. 2012 Sep;7:e43994; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9; Kwong A et al. J. Mol. Diagn. 2016 Jul;18(4):580-94; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zhao Q et al. J. Gynecol. Oncol. 2017 Jul;28(4):e39; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). This mutation has also been reported in male patients with breast cancer and in a male patient with biliary tract cancer (Fostira F et al. Breast Cancer Res Treat. 2018 May;169(1):105-113; Wardell CP et al. J Hepatol. 2018 May;68(5):959-969; Momozawa Y et al. Nat Commun. 2018 Oct 4;9(1):4083). This mutation, in compound heterozygosity with another BRCA2 mutation, was also detected in a child with clinical features of Fanconi anemia (Kopic S et al. Acta Paediatr. 2011 May;100:780-3). Of note, this alteration is also designated as 9325insA and 9325dupA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031791	SCV000196022	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000045711	SCV000210799	pathogenic	not provided	2024-04-10	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 9150172, 12161607, 22798144, 25940717, 23569316, 29335925, 35264596); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9325dupA, 9317insA, or 9089_9090insA; This variant is associated with the following publications: (PMID: 12161607, 26852015, 26843898, 35534704, 32073954, 36555431, 34284872, 36637704, 36243179, 36721989, 34196900, 35864222, 28324225, 27882536, 32772980, 32599251, 32875559, 29922827, 9150172, 22970155, 21138478, 21913181, 23569316, 22798144, 18489799, 23242139, 25940717, 27157322, 27393621, 20383589, 25330149, 29752822, 29907814, 28692638, 28541631, 29335925, 28993434, 29310832, 30720863, 30287823, 30720243, 30702160, 30093976, 31159747, 31396961, 30736435, 31957001, 32072338, 32029870, 31214711, 32846166, 31589614, 31825140, 33558524, 32338768, 30875412, 30613976, 31742824, 32959997, 31360904, 31723001, 35418818, 33804961, 29360550, 31209999, 28724667, 35264596)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210094	SCV000266049	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000045711	SCV000296658	pathogenic	not provided	2023-07-26	criteria provided, single submitter	clinical testing	The BRCA2 c.9097dup (p.Thr3033Asnfs*11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 33558524 (2021), 32959997 (2020), 32846166 (2020), 22970155 (2012), ovarian cancer (PMID: 28541631 (2017)), and pancreatic cancer (PMID: 259407172015)). The variant has also been reported in a child with Fanconi Anemia (PMID: 21138478 (2011)). The frequency of this variant in the general population, 0.000012 (3/245952 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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	RCV000031791	SCV000328046	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031791	SCV000488294	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195406	SCV000605794	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Thr3033AsnfsX11 variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Serova-Sinilnikova 1997, Kopic 2011, Kwong 2012, Holter 2015, Wong-Brown 2015, Breast Cancer Information Core (BIC) database). This variant has been identified in 1/15908 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3033 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282467.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PM2.
Color Diagnostics, LLC DBA Color Health	RCV000130439	SCV000684022	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 23 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9325insA, 9317insA and c.9090insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals and families affected with breast and ovarian cancer (PMID: 9150172, 18489799, 22798144, 22970155, 24010542, 24916970, 25682074, 28541631, 28692638, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001002) and additional individuals affected with pancreatic, prostate and biliary tract cancer (PMID: 25940717, 29360550, 31214711). This variant has been described as a recurrent mutation in hereditary breast and ovarian cancer families in the Chinese population (PMID: 22970155). This variant has also been reported in the compound heterozygous state in an individual affected with Fanconi anaemia (PMID: 21138478). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
GeneKor MSA	RCV000585671	SCV000693591	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change duplicates one base in exon 23 of BRCA2 mRNA (c.9097dupA), causing a frameshift after codon 3033 and the creation of a premature translation stop signal 11 amino acid residues later p.(Thr3033Asnfs*11). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as c.9097_9098insA, 9325insA and 9317insA in the literature and has been reported in individuals affected with breast and ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 22970155 , PMID: 9150172 PMID: 25940717 , PMID: 21138478). The mutation database ClinVar contains entries for this variant (Variation ID: 38208).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195406	SCV000695208	pathogenic	Hereditary breast ovarian cancer syndrome	2017-06-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000195406	SCV000838892	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000045711	SCV002047738	pathogenic	not provided	2021-07-03	criteria provided, single submitter	clinical testing	The BRCA2 c.9097dupA; p.Thr3033AsnfsTer11 variant (rs397507419) has been reported in multiple individuals with breast or ovarian cancer (Kim 2012, Kwong 2012, Machackova 2008, Serova-Sinilnikova 1997, Zhao 2017). It is reported as pathogenic in ClinVar (Variation ID: 38208), and is only observed on 3 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant introduces a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Kim H et al. Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. Breast Cancer Res Treat. 2012; 134(3):1315-26. Kwong A et al. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. PLoS One. 2012; 7(9):e43994. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008; 8:140. Serova-SInilnikova O et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997; 60(5):1236-9. Zhao Q et al. Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000045711	SCV002051549	pathogenic	not provided	2020-12-30	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
MGZ Medical Genetics Center	RCV000031791	SCV002579332	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-07-16	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV002463351	SCV002757839	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2	2020-10-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000045711	SCV002760735	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Heidelberg University	RCV000031791	SCV003936056	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-13	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000045711	SCV004025947	pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing	PVS1, PP4, PM2_SUP
Baylor Genetics	RCV000031791	SCV004041489	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-01	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV003334379	SCV004042782	pathogenic	See cases	2023-03-31	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1, PS4_MOD, PM2_SUP
Baylor Genetics	RCV000585671	SCV004211832	pathogenic	Familial cancer of breast	2024-03-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000045711	SCV004238329	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735619	SCV004240374	pathogenic	Breast and/or ovarian cancer	2023-04-28	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000045711	SCV005196954	pathogenic	not provided	2024-03-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000210094	SCV005368292	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-06-26	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
Sharing Clinical Reports Project (SCRP)	RCV000031791	SCV000054399	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-03-01	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000195406	SCV000587986	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353615	SCV000592254	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr3033Asnfs*11 variant was identified in 9 of 10056 proband chromosomes (frequency: 0.0009) from Australian, Polish, French, Czech, Chinese, Greek and Korean individuals or families with triple negative breast cancer, (high risk) breast or ovarian cancer, HBOC, or pancreatic cancer (Wong 2015, Serova-Sinilnicova 1997, Machackova 2008, Kwong 2012, Konstantopoulou 2014, Kang 2015, Holter 2015). The variant was also identified in a 4 year old with Fanconi anemia with a hepatoblastoma (Kopic 2010). The variant was identified in dbSNP (ID: rs754205122) as “With Pathogenic allele”, in ClinVar (as pathogenic, reviewed by an expert panel 2016 with 15 submitters), Clinvitae (7x), COGR (2x clinical laboratories), Cosmic (1x in a colon adenocarcinoma), LOVD 3.0 (1x), UMD-LSDB (19x as Causal, and as co-occurring with a pathogenic BRCA1 variant: c.3756_3759delGTCT, p.Ser1253ArgfsX10), BIC Database (27x with clinical importance classified pathogenic), and ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in MutDB, or Zhejiang University database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9097dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3033 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735619	SCV000863757	pathogenic	Breast and/or ovarian cancer	2013-06-08	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785367	SCV000923938	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000585671	SCV000925778	pathogenic	Familial cancer of breast	2018-09-27	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV000585671	SCV000987249	pathogenic	Familial cancer of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr3033Asnfs is a known pathogenic variant in exon 23 in the Nucleic acid-binding OB-fold (T2968-3184L aa) domain, which binds to single-stranded nucleic acids (staphylococcal nuclease and aspartyl-tRNA synthetase) or oligosaccharides (B subunits of enterotoxin and verotoxin-1), and has been termed the oligonucleotide/oligosaccharide binding motif, or OB fold (PMID: 12769718). This frameshift mutation disrupts the function of the domain which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This mutation hotspot has 31 pathogenic variants (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282467.1) (PP5 Pathogenic Supporting). The variant p.Thr3033Asnfs was found in a 48-year-old female with unilateral breast cancer and a strong family history.
CZECANCA consortium	RCV000735619	SCV001451888	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554255	SCV001774855	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000045711	SCV001906053	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000045711	SCV001954348	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000045711	SCV001966901	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162285	SCV002758299	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Department Of Pathology & Laboratory Medicine, University Of Pennsylvania	RCV003448973	SCV004176811	pathogenic	Malignant lymphoma, large B-cell, diffuse	2023-12-04	no assertion criteria provided	clinical testing	Post-initial therapy specimen.
BRCAlab, Lund University	RCV000031791	SCV004243851	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing