Submissions for variant NM_000059.4(BRCA2):c.8067T>A (p.Cys2689Ter)

dbSNP: rs80359046

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113864	SCV000301240	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.
Counsyl	RCV000113864	SCV000220678	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-09-09	criteria provided, single submitter	literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113864	SCV000327812	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000416520	SCV000494293	pathogenic	Hereditary breast ovarian cancer syndrome	2022-07-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8067T>A (p.Cys2689X) 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 251244 control chromosomes. c.8067T>A 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. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000571445	SCV000673071	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	The p.C2689* pathogenic mutation (also known as c.8067T>A), located in coding exon 17 of the BRCA2 gene, results from a T to A substitution at nucleotide position 8067. This changes the amino acid from a cysteine to a stop codon within coding exon 17. This variant has been reported in studies of patients with suspected hereditary breast and/or ovarian cancer and in a patient with Fanconi anemia (Stratton M et al. Lancet 1997 May; 349(9064):1505-10; Peelen T et al. Br. J. Cancer 2000 Jan; 82(1):151-6.;Litton JK et al. Cancer 2012 Jan; 118(2):321-5; Bayraktar S et al. Cancer 2012 Mar; 118(6):1515-22; Ameziane N et al. Anemia 2012; 2012:132856; Vos JR et al. Cancer Epidemiol. Biomarkers Prev. 2014 Nov; 23(11):2482-91). 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113864	SCV000743340	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	RCV000113864	SCV000744531	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000657589	SCV000779326	pathogenic	not provided	2016-07-19	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8067T>A at the cDNA level and p.Cys2689Ter (C2689X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Using alternate nomenclature, this variant would be defined as BRCA2 8295T>A and has been reported in multiple individuals with personal and family histories consistent with hereditary breast cancer (Breast Cancer Linkage Consortium 1997, Litton 2000, Peelen 2000, van der Hout 2006, Bayraktar 2012). We consider this variant to be pathogenic.
Mendelics	RCV000416520	SCV000838866	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000416520	SCV002025840	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Invitae	RCV000416520	SCV002234338	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52493). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast or ovarian cancer (PMID: 9167459, 10638982, 22009639, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys2689*) 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).
Baylor Genetics	RCV003473414	SCV004212871	pathogenic	Familial cancer of breast	2021-12-07	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113864	SCV000147263	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113864	SCV000733312	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000657589	SCV001905912	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000657589	SCV001956711	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113864	SCV004243800	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing