Submissions for variant NM_000059.4(BRCA2):c.9294C>G (p.Tyr3098Ter)

gnomAD frequency: 0.00002  dbSNP: rs80359200

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031812	SCV000282471	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	RCV000045784	SCV000073797	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr3098*) 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 (rs80359200, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12698193, 23569316, 24728189, 26787237, 26845104). This variant is also known as 9522C>G. ClinVar contains an entry for this variant (Variation ID: 38229). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074562	SCV000108647	pathogenic	not provided	2023-07-20	criteria provided, single submitter	clinical testing	Nonsense 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 many individuals with personal and/or family history of BRCA2-related cancers (Frank et al., 1998; Lubinski et al., 2004; Kurian et al., 2008; Kwong et al., 2016; Rummel et al., 2017; Sun et al., 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 9522C>G; This variant is associated with the following publications: (PMID: 18779604, 25525159, 27067391, 27157322, 15131399, 12698193, 9667259, 26681312, 26845104, 15695382, 27456091, 28503720, 28454591, 28242752, 28724667, 28993434, 31263054, 29487695, 29446198, 30720243, 34399810, 31447099, 33804961, 30702160, 32468491, 33087929, 30274973, 31825140, 30787465, 32782288, 31892343, 33758026, 31723001, 28888541, 34761457, 29922827)
Ambry Genetics	RCV000131041	SCV000185971	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	The p.Y3098* pathogenic mutation (also known as c.9294C>G), located in coding exon 24 of the BRCA2 gene, results from a C to G substitution at nucleotide position 9294. This changes the amino acid from a tyrosine to a stop codon within coding exon 24. This alteration has been reported in numerous studies, including large hereditary breast and ovarian cancer cohort studies, and has been identified in patients with breast, ovarian, prostate and pancreatic cancers (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Scottish/Northern Irish BRCA1/BRCA2 Consortium. Br. J. Cancer. 2003 Apr;88:1256-62; Kurian AW et al. J. Clin. Oncol. 2008 Oct;26:4752-8; Castro E et al. J Clin Oncol, 2013 May;31:1748-57; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Kerr L et al. BMC Cancer. 2016 07;16:529; Shirts BH et al. Genet Med, 2016 10;18:974-81; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 9522C>G 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	RCV000210096	SCV000266052	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031812	SCV000328102	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031812	SCV000488714	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000465472	SCV000540995	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000045784	SCV000592274	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131041	SCV000684052	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 25 of the BRCA2 gene, creating a 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 9 individuals affected with breast or ovarian cancer (PMID: 9667259, 24728189, 25186627, 26787237, 28724667, 33471991; Leiden Open Variation Database DB-ID BRCA2_001528) and dozens of suspected hereditary breast and ovarian cancer families (PMID: 12698193, 16234499, 18779604, 26187060, 30702160). This variant also has been reported in individuals affected with pancreatic and prostate cancer (PMID: 23569316, 26845104, 27456091, 30274973). This variant has been identified in 3/282252 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045784	SCV000695234	pathogenic	Hereditary breast ovarian cancer syndrome	2017-03-24	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9294C>G (p.Tyr3098X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.9331G>T [p.Glu3111X], c.9382C>T [p.Arg3128X], and c.9403delC [p.Leu3135fsX28]). The variant lies within a nucleic acid-binding, OB-fold domain (InterPro) and one in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120548 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Several publications cite the variant in patients and classify it as a pathogenic mutation (e.g., Kwong_BRCA_JMG_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031812	SCV000839911	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-27	criteria provided, single submitter	clinical testing	A heterozygous c.9294C>G (p.Tyr3098*) pathogenic variant in the BRCA2 gene was detected in this individual. This variant has been previously described in multiple individuals with breast, ovarian, prostate and pancreatic cancer (PMID: 12698193, 24728189, 26787237, 23569316, 26845104).Therefore, we consider this variant to be pathogenic. [alaimo, 2018-01-30]
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000031812	SCV000883122	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-11-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000074562	SCV000885085	pathogenic	not provided	2018-01-25	criteria provided, single submitter	clinical testing	The BRCA2 c.9294C>G; p.Tyr3098Ter variant (rs80359200), also known as 9522C>G, is reported in the literature in individuals and families with hereditary breast and ovarian cancer syndrome (Lubinski 2004, Scottish/Northern Irish BRCA1/BRCA2 Consortium 2003), and is classified as pathogenic in ClinVar (Variation ID: 38229). This variant is found in the general population with a low overall allele frequency of 0.001% (3/276620 alleles) in the Genome Aggregation Database. This variant induces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered pathogenic. References: Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Scottish/Northern Irish BRCAI/BRCA2 Consortium. BRCA1 and BRCA2 mutations in Scotland and Northern Ireland. Br J Cancer. 2003;88(8):1256-62.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074562	SCV000887959	pathogenic	not provided	2020-06-30	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in families affected with breast/ovarian cancer in the published literature (PMID: 25186627 (2015), 29446198 (2018), 30702160 (2019)) as well as in a pancreatic cancer patient (PMID: 30274973 (2018)). Based on the available information, the variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763331	SCV000894008	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	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000074562	SCV002023651	pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000045784	SCV002515163	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000210096	SCV003799077	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-10-07	criteria provided, single submitter	clinical testing	PVS1, PS4
Sharing Clinical Reports Project (SCRP)	RCV000031812	SCV000054420	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-01-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031812	SCV000147604	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	RCV000045784	SCV000587997	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031812	SCV004243865	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing