Submissions for variant NM_000059.4(BRCA2):c.1889del (p.Thr630fs)

dbSNP: rs80359315

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077271	SCV000300476	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	RCV000043918	SCV000071931	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr630Asnfs*14) 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 cancer and prostate cancer (PMID: 20736950, 25682074). This variant is also known as 2117delC. ClinVar contains an entry for this variant (Variation ID: 51221). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000221409	SCV000277553	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing	The c.1889delC pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1889, causing a translational frameshift with a predicted alternate stop codon (p.T630Nfs*14). This mutation has been reported in a cohort of men with prostate cancer undergoing clinical BRCA1/2 testing, as well as in a woman with triple negative breast cancer at age 48 and a mother with breast cancer at age 39 (Edwards SM et al. Br. J. Cancer 2010 Sep;103(6):918-24; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150(1):71-80). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620) and in an individual undergoing pancreatic cancer screening due to a family history of breast and ovarian cancer (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077271	SCV000326631	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000478099	SCV000568458	pathogenic	not provided	2023-02-22	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 breast and prostate cancer (Edwards et al., 2010; Wong-Brown et al., 2015; Davies et al., 2017; Lerner-Ellis et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2117delC; This variant is associated with the following publications: (PMID: 26269718, 28288110, 20736950, 29371908, 25682074, 32918181, 30787465, 32885271)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043918	SCV000694582	pathogenic	Hereditary breast ovarian cancer syndrome	2016-09-08	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1889delC (p.Thr630Asnfs) 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.1929delG (p.Arg645fs), c.2103_2106delTATT (p.Phe701fs), and c.2212dupT (p.Cys738fs). The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications and databases. In addition, multiple clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
Color Diagnostics, LLC DBA Color Health	RCV000221409	SCV001355367	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-26	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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 individuals with a personal or family history of breast, ovarian, or prostate cancer (PMID: 20736950, 25682074, 27153395, 29371908, 30883245, Color internal data). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_004294). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478099	SCV002046173	pathogenic	not provided	2020-11-13	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 affected with breast cancer and prostate cancer in the published literature (PMID: 20736950 (2010) and 25682074 (2015)). Therefore, the variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002477143	SCV002778322	likely pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Prostate cancer; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-02-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460564	SCV004214576	pathogenic	Familial cancer of breast	2021-05-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005357294	SCV005915472	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2	2019-10-24	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077271	SCV000109068	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-04-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077271	SCV000145973	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000043918	SCV000587618	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research