Submissions for variant NM_000059.4(BRCA2):c.9253dup (p.Thr3085fs)

dbSNP: rs80359752

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031808	SCV000301365	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195407	SCV000073773	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr3085Asnfs*26) 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). This variant is present in population databases (rs80359752, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 11389159, 16455195, 16683254, 19656164, 21952622, 22798144, 23569316, 25330149). This variant is also known as 9474insA, 9481insA, 9253insA, and c.9253_9254insA. ClinVar contains an entry for this variant (Variation ID: 38225). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130780	SCV000185673	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-18	criteria provided, single submitter	clinical testing	The c.9253dupA pathogenic mutation, located in coding exon 23 of the BRCA2 gene, results from a duplication of A at nucleotide position 9253, causing a translational frameshift with a predicted alternate stop codon (p.T3085Nfs*26). This alteration has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Pal T et al. Cancer. 2015 Dec;121:4173-80). This mutation has also been detected in a male with early-onset prostate cancer (Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;1051230-4) and in a male breast cancer patient (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). Of note, this alteration is also designated as c.9253insA, c.9253_9254insA, and c.9474insA 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.
GeneDx	RCV000045760	SCV000210800	pathogenic	not provided	2020-09-11	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 9481insA, 9481dupA, and 9474insA; This variant is associated with the following publications: (PMID: 22798144, 23034506, 16455195, 26287763, 21120943, 25330149, 30702160, 30322717, 32854451, 23569316, 11920643, 20104584, 19656164, 18824701, 11389159, 16683254, 21952622, 26681312, 25863477, 22720145, 28008555, 27836010, 28152038, 11802209, 7627958, 30972954, 29310832, 28724667, 29915322, 29339979, 30720243, 31396961, 29625052, 31447099, 32832836)
Counsyl	RCV000031808	SCV000220419	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-06-16	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000130780	SCV000292174	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9246_9247insA, 9474insA and 9481insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 11389159, 16683254, 20104584, 22798144, 25330149, 25863477, 26287763, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001724) and two individuals affected with prostate cancer (PMID: 23569316). This variant has been identified in 2/243602 chromosomes 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031808	SCV000328084	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477040	SCV000575733	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-09-13	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000195407	SCV000588127	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031808	SCV000605645	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195407	SCV000695224	pathogenic	Hereditary breast ovarian cancer syndrome	2020-09-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9253dupA (p.Thr3085AsnfsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 248942 control chromosomes. c.9253dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Bergthorsson_2001, Inoue_1997, Kim_2012, Pal_2015, Rebbeck_2016). These data indicate that the variant is very likely to be associated with disease. At-least one trans heterozygous co-occurrence with another pathogenic variant has been reported (BRCA1 c.3226_3227AG (reported as NM_007294:c.3228_3229delAG), p.Gly1077fs) (Rebbeck_2016). Thirteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031808	SCV000744559	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031808	SCV000839929	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-27	criteria provided, single submitter	clinical testing	The c.9246_9247dupA (p.Thr3085Asnfs*26) frameshift variant in BRCA2 has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 11389159, 16455195, 16683254, 21952622,22798144, 25330149]. Based on the current evidence, this variant is classified as pathogenic
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000045760	SCV000889181	pathogenic	not provided	2020-10-11	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, it has been reported in individuals affected with breast and/or ovarian cancer, prostate cancer, and esophageal cancer (PMIDs: 11389159 (2001), 21952622 (2011), 22798144 (2012), 29915322 (2018), 30322717 (2018), 31396961 (2019), 30702160 (2019), and 30972954 (2019)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV003473229	SCV004211803	pathogenic	Familial cancer of breast	2024-03-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000045760	SCV004243077	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031808	SCV004846143	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-08	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9246_9247insA, 9474insA and 9481insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 11389159, 16683254, 20104584, 22798144, 25330149, 25863477, 26287763, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001724) and two individuals affected with prostate cancer (PMID: 23569316). This variant has been identified in 2/243602 chromosomes 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031808	SCV005045996	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Sharing Clinical Reports Project (SCRP)	RCV000031808	SCV000054416	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-12-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031808	SCV000147581	pathogenic	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	RCV000195407	SCV000587992	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031808	SCV000733335	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Gharavi Laboratory, Columbia University	RCV000045760	SCV000809461	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785231	SCV000923799	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000045760	SCV001554114	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Thr3085AsnfsX26 variant was identified in 13 of 20330 proband chromosomes (frequency: 0.0006) from German, Danish, Korean, American, and British individuals or families with (sporadic, high risk, early onset, or male) breast cancer, sporadic or familial ovarian cancer or prostate cancer (Meindl_2002_11802209, Bergthorsson_2001_11389159, Kang_2015_25863477 , Kim_2012_22798144, Pal_2015_26287763 , Pritzlaff_2016_28008555, Kote-Jarai_2011_21952622, Rebbeck_2016_27836010, Borg_2010_20104584, Cybulski_2015_25330149). In a study looking at transheterozygosity (inheritance of pathogenic mutations in both BRCA1 and BRCA2), the variant was identified in 1 Italian proband with breast cancer, co-occurring with BRCA1 c.3228_3229delAG (Rebbeck_2016_27836010). The variant was also identified in dbSNP (ID: rs80359752) “With Pathogenic allele”, ClinVar (classified pathogenic, reviewed by an expert panel (2016); submitters: pathogenic by ENIGMA, CIMBA, Fulgent Genetics, Ambry Genetics, GeneDx, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, Invitae, Dept. of Medical Genetics (Oslo University Hospital), BIC and SCRP (Sharing Clinical Reports Project); and likely pathogenic by Counsyl), Clinvitae (4x), GeneInsight-COGR (classified pathogenic by 2 clinical laboratories), LOVD 3.0 (1x), UMD-LSDB (5x causal), BIC Database (19x, with clinical importance, class 5 (pathogenic)), ARUP Laboratories (5-definitely pathogenic), Zhejiang Colon Cancer Database; the variant was not identified in Cosmic, MutDB, 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.9253dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3085 and leads to a premature stop codon at position 3110. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000045760	SCV001926450	pathogenic	not provided		no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000031808	SCV004022193	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-21	no assertion criteria provided	research	The variant NM_000059.4:c.9253dup (chr13:32380135) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.
BRCAlab, Lund University	RCV000031808	SCV004243861	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541052	SCV004759088	pathogenic	BRCA2-related disorder	2024-07-24	no assertion criteria provided	clinical testing	The BRCA2 c.9253dupA variant is predicted to result in a frameshift and premature protein termination (p.Thr3085Asnfs*26). This variant (also reported as 9253insA, 9481dupA & 9474insA) has been reported in many individuals with various cancers, including breast/ovarian cancer (Bergthorsson et al. 2001. PubMed ID: 11389159; Table S1, Borg et al. 2010. PubMed ID: 20104584; Table 4, Kim et al. 2012. PubMed ID: 22798144; Table S1, Carter et al. 2018. PubMed ID: 30322717), prostate cancer (Table A1, Castro et al. 2013. PubMed ID: 23569316; Table S2, Matejcic et al. 2020. PubMed ID: 32832836), biliary tract cancer (Power et al. 2020. PubMed ID: 32918181), lung and esophageal squamous cell carcinoma (Table S2A, Huang et al. 2018. PubMed ID: 29625052), and renal cell carcinoma (Yngvadottir et al. 2022. PubMed ID: 35441217). It has also been reported as pathogenic by multiple sources in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38225/). This variant is reported in 0.00089% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.