Submissions for variant NM_000059.4(BRCA2):c.8904del (p.Val2969fs)

dbSNP: rs80359730

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031775	SCV000282464	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.
Invitae	RCV000045650	SCV000073663	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val2969Cysfs*7) 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 prostate cancer and a personal and/or family history of breast cancer (PMID: 9667259, 15026808, 21952622, 23035815, 28284943). This variant is also known as 9132delC. ClinVar contains an entry for this variant (Variation ID: 38192). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131370	SCV000186346	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-10	criteria provided, single submitter	clinical testing	The c.8904delC pathogenic mutation, located in coding exon 21 of the BRCA2 gene, results from a deletion of one nucleotide at position 8904, causing a translational frameshift with a predicted alternate stop codon (p.V2969Cfs*7). This mutation was previously identified in a patient with early-onset breast cancer who had a family history of breast cancer (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25), as well as in individuals diagnosed with prostate cancer (Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4; Willems-Jones A et al. BJU Int. 2012 Dec;110(11 Pt C):E1181-6; Cheng HH et al. Eur. Urol. 2016 Jun;69:992-5). This alteration has also been seen as a recurrent mutation in breast and/or ovarian cancer families of Belgian descent (Claes K et al. Br. J. Cancer. 2004 Mar;90:1244-51; Janaviius R. EPMA J. 2010 Sep;1:397-412). Of note, this alteration is also designated as 9132delC 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	RCV000031775	SCV000267823	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000216861	SCV000278884	pathogenic	not provided	2022-06-01	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Frank 1998, Lalloo 2003, Kote-Jarai 2011, Willems-Jones 2012, Castro 2013, Cheng 2016); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9132delC; This variant is associated with the following publications: (PMID: 12672316, 15026808, 21952622, 9667259, 23199084, 23569316, 23035815, 15131399, 26724258, 27225637, 32338768, 33654310, 33087929, 30787465, 32885271, 32853339)
Color Diagnostics, LLC DBA Color Health	RCV000131370	SCV000292151	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 22 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 at least 11 individuals affected with breast or ovarian cancer (PMID: 9667259, 10359546, 12750261, 15635067, 18445692, 18563556, 20807450, 22711857, 25186627, 28831036) and in a breast cancer case-control meta-analysis in 6/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001079). This variant also has been reported in several dozens of individuals and families suspected of being affected with hereditary breast and ovarian cancer (PMID: 12920083, 12960223, 15026808, 16234499, 20815029, 29446198) and in individuals affected with prostate cancer (PMID: 18445692, 21952622, 23035815, 23569316, 26724258). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735615	SCV000324883	pathogenic	Breast and/or ovarian cancer	2016-02-11	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031775	SCV000327985	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	RCV000045650	SCV000586987	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000045650	SCV000588123	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216861	SCV000600830	pathogenic	not provided	2021-07-23	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with breast/ovarian cancer or prostate cancer in the published literature (PMID: 15026808 (2004), 21952622 (2011), 23035815 (2012), 26724258 (2016)). Based on the available information, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045650	SCV000605797	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Val2969CysfsX7 variant in BRCA2 has been reported at least 40 individuals with BRCA2-associated cancers (Claes 2004, Kote-Jarai 2011, Frank 1998, Breast Cancer Information Core (BIC) database), and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2969 and leads to a premature termination codon 7 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 SCV000282464.1). In summary, the p.Val2969CysfsX7 variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PM2.
PreventionGenetics, part of Exact Sciences	RCV000216861	SCV000805789	pathogenic	not provided	2018-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045650	SCV000918986	pathogenic	Hereditary breast ovarian cancer syndrome	2021-01-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8904delC (p.Val2969CysfsX7) 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 was absent in 249760 control chromosomes. c.8904delC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories, one consortium (CIMBA) and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000216861	SCV001160334	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	The BRCA2 c.8904delC; p.Val2969CysfsTer7 variant (rs80359730), also known as 9132delC for traditional nomenclature, is reported in the literature in individuals with breast, ovarian, or prostate cancer (Claes 2004, Frank 1998, Kote-Jarai 2011). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 38192). It is absent from general population databases (Exome Variant Server, 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: Claes K et al. BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer. 2004 Mar 22;90(6):1244-51. Frank TS et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998 Jul;16(7):2417-25. Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011 Oct 11;105(8):1230-4.
Mayo Clinic Laboratories, Mayo Clinic	RCV000216861	SCV001714438	pathogenic	not provided	2020-02-21	criteria provided, single submitter	clinical testing	PVS1, PS4_Mod, PM2, PP5
Sema4, Sema4	RCV000131370	SCV002531985	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV002272034	SCV002556903	pathogenic	Familial cancer of breast	2021-11-26	criteria provided, single submitter	clinical testing	The BRCA2 c.8904delC variant is classified as Pathogenic (PVS1, PM2) This BRCA2 c.8904delC variant is located in exon 22/27 and is predicted to cause a shift in the reading frame at codon 2969. The variant is rare in population databases and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 38192).
Fulgent Genetics, Fulgent Genetics	RCV002482935	SCV002800844	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	2022-05-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000216861	SCV003815003	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002272034	SCV004213680	pathogenic	Familial cancer of breast	2023-08-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031775	SCV004846089	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 22 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 at least 11 individuals affected with breast or ovarian cancer (PMID: 9667259, 10359546, 12750261, 15635067, 18445692, 18563556, 20807450, 22711857, 25186627, 28831036) and in a breast cancer case-control meta-analysis in 6/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001079). This variant also has been reported in several dozens of individuals and families suspected of being affected with hereditary breast and ovarian cancer (PMID: 12920083, 12960223, 15026808, 16234499, 20815029, 29446198) and in individuals affected with prostate cancer (PMID: 18445692, 21952622, 23035815, 23569316, 26724258). 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.
Sharing Clinical Reports Project (SCRP)	RCV000031775	SCV000054383	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-12-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031775	SCV000147482	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	RCV000045650	SCV000587975	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353455	SCV000592235	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2, p.Val2969CysfsX7 variant was identified in 4 of 5018 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian and prostate cancer (De Leeneer 2010, Evans 2003, Frank 1998, Kote-Jarai 2011). The variant was also identified in dbSNP (ID: rs80359730) “With pathogenic allele”, HGMD, the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports; BIC and Ambry Genetics), GeneInsight VariantWire database (2X, classified as “pathogenic” by a clinical laboratory) and the BIC database (37X with clinical importance).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. The p.Val2969CysfsX7 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2969 and leads to a premature stop codon 7 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	RCV000735615	SCV000863753	pathogenic	Breast and/or ovarian cancer	2015-09-11	no assertion criteria provided	clinical testing