Submissions for variant NM_000059.4(BRCA2):c.8297del (p.Thr2766fs)

gnomAD frequency: 0.00001  dbSNP: rs80359705

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031732	SCV000282457	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	RCV000034463	SCV000073479	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr2766Asnfs*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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian and/or prostate cancer (PMID: 8589730, 10682686, 12960223, 20736950, 23028338, 25085752, 26681312). This variant is also known as 8525delC. ClinVar contains an entry for this variant (Variation ID: 38149). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000045466	SCV000210793	pathogenic	not provided	2022-01-27	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 and/or family history of BRCA2-related cancers (Tavtigian 1996, Evans 2003, Edwards 2010, Willems-Jones 2012, McVeigh 2014, Pritzlaff 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8525delC; This variant is associated with the following publications: (PMID: 12474142, 20736950, 12960223, 30609409, 12181777, 26046366, 25682074, 26681312, 23035815, 23884708, 8589730, 23028338, 28008555, 25085752, 22703879, 26845104, 31090900, 26295337, 25685387, 23569316, 10682686, 31569370, 32853339, 30787465, 33087929)
Ambry Genetics	RCV000163359	SCV000213895	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	clinical testing	The c.8297delC pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8297, causing a translational frameshift with a predicted alternate stop codon (p.T2766Nfs*11). This mutation was reported in one family with multiple cases of female and male breast cancer and ovarian cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7). This alteration has also been reported in multiple men diagnosed with prostate cancer before the age of 55 (Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Willems-Jones A et al. BJU Int. 2012 Dec;110:E1181-6; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57). Of note, this alteration is also designated as 8525delC 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210122	SCV000266047	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031732	SCV000267818	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000045466	SCV000296689	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	The BRCA2 c.8297del (p.Thr2766Asnfs*11) variant has been reported in the published literature in individuals and families affected with breast and/or ovarian cancer (PMIDs: 8589730 (1996), 10682686 (2000), 26681312 (2015)) and prostate cancer (PMIDs: 20736950 (2010), 23569316 (2013)). The frequency of this variant in the general population, 0.0000066 (1/152178 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	RCV000031732	SCV000327853	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000034463	SCV000586981	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163359	SCV000683953	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 18 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 9 individuals affected with breast or ovarian cancer (PMID: 10682686, 12960223, 23146383, 25682074, 26681312, 26845104, 33471991), 3 individuals affected with prostate cancer (PMID: 20736950, 23569316), and 1 unaffected individual (PMID: 33471991). This variant has been identified in 70 families among the CIMBA participants (PMID: 29446198). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034463	SCV000695139	pathogenic	Hereditary breast ovarian cancer syndrome	2016-07-01	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.8297delC (p.Thr2766Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP). Multiple publications cite the variant in affected individuals, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031732	SCV000778589	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-16	criteria provided, single submitter	research
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163359	SCV000803159	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000034463	SCV000966960	pathogenic	Hereditary breast ovarian cancer syndrome	2018-02-22	criteria provided, single submitter	clinical testing	The p.Thr2766AsnfsX11 (NM_000059.3 c.8297delC) variant in BRCA2 (also referred t o as c.8285delC in the literature) has been previously reported in many individu als and families with breast, ovarian or prostate cancer (Tavtigian 1996, Castro 2013, McVeigh 2014, Wong-Brown 2015), and was absent from large population stud ies. In addition, this variant was classified as Pathogenic by the ClinGen-appr oved ENIGMA expert panel (ClinVar SCV000282457.1). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2766 and leads to a premature termination codon 11 amino acids downstre am. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in here ditary breast and ovarian cancer syndrome (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant m anner based on its occurrence in affected individuals and its predicted impact t o the protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PP5 (Richards 2015).
Sema4, Sema4	RCV000163359	SCV002531929	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002477039	SCV002780679	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	2022-03-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000045466	SCV003810423	pathogenic	not provided	2023-04-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473217	SCV004211850	pathogenic	Familial cancer of breast	2024-02-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000045466	SCV004565285	pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	The BRCA2 c.8297del; p.Thr2766AsnfsTer11 variant (rs80359705), also known as 8525delC, is reported in individuals with hereditary breast and ovarian cancer syndrome (Edwards 2010, Lilyquist 2017, Tavtigian 1996). This variant is also reported in ClinVar (Variation ID: 38149). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 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 to be pathogenic. References: Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. PMID: 20736950. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Tavtigian SV et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333-7. PMID: 8589730.
All of Us Research Program, National Institutes of Health	RCV000031732	SCV004845630	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-06	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 18 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 9 individuals affected with breast or ovarian cancer (PMID: 10682686, 12960223, 23146383, 25682074, 26681312, 26845104, 33471991), 3 individuals affected with prostate cancer (PMID: 20736950, 23569316), and 1 unaffected individual (PMID: 33471991). This variant has been identified in 70 families among the CIMBA participants (PMID: 29446198). 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.
OMIM	RCV000031732	SCV000030129	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1996-03-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034463	SCV000043230	pathogenic	Hereditary breast ovarian cancer syndrome	2012-07-13	no assertion criteria provided	research	Converted during submission to Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031732	SCV000054339	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031732	SCV000147316	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	RCV000034463	SCV000587944	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004532459	SCV004729565	pathogenic	BRCA2-related disorder	2023-11-16	no assertion criteria provided	clinical testing	The BRCA2 c.8297delC variant is predicted to result in a frameshift and premature protein termination (p.Thr2766Asnfs*11). This variant (also known as 8525delC) has been reported in individuals with breast, ovarian, or prostate cancer (Table 1, Tavtigian et al. 1996. PubMed ID: 8589730; Table 1, Edwards et al. 2003. PubMed ID: 12474142; Table 1, Edwards et al. 2010. PubMed ID: 20736950, Table 2, Wong-Brown et al. 2015. PubMed ID: 25682074; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reviewed by an expert panel and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38149/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.