Submissions for variant NM_000059.4(BRCA2):c.1796_1800del (p.Thr598_Ser599insTer)

dbSNP: rs276174813

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031337	SCV000282361	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	RCV000168232	SCV000071900	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser599*) 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 (rs276174813, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 8988179, 22009639, 22085629, 22798144, 24549055). This variant is also known as c.1796delCTTAT and 2024del5. ClinVar contains an entry for this variant (Variation ID: 37756). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129987	SCV000184811	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	clinical testing	The c.1796_1800delCTTAT pathogenic mutation (also known as p.S599*), located in coding exon 9 of the BRCA2 gene, results from a deletion of five nucleotides at positions 1796 to 1800. This changes the amino acid from a serine to a stop codon within coding exon 9. This mutation has been detected in female breast cancer, male breast cancer, and ovarian cancer cases (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Ladopoulou A et al. Cancer Lett. 2002 Nov;185:61-70; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Torres-Mejia G et al. Cancer Epidemiol. Biomarkers Prev. 2015 Mar;24:498-505; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169:105-113; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24:326-333). Of note, this alteration is also designated as 2024del5 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.
GeneDx	RCV000043887	SCV000210716	pathogenic	not provided	2023-05-11	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; 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 2024_2028del, 2024del5, and c.1794_1798del; This variant is associated with the following publications: (PMID: 12142080, 29470806, 30014164, 31794323, 31336956, 34413315, 32438681, 32875559, 30040829, 8988179, 22009639, 22085629, 24549055, 11754111, 27062684, 28724667, 29907814, 29084914, 29335925, 25371446, 22798144, 18694767, 15887246, 11504767, 9150154, 26295337, 22762150, 31209999, 30720243, 30702160, 31396961, 31444830, 31957001, 31447099, 33726785, 31825140, 30787465, 31742824, 30130155, 34645131, 35535697, 32427313, 31871109)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031337	SCV000326611	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031337	SCV000677720	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129987	SCV000683449	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides 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 at least 15 individuals affected with breast, ovarian and/or endometrial cancer (PMID: 9150154, 11754111, 12142080, 15887246, 18694767, 18752448, 22009639, 25371446, 29084914, 33471991; Leiden Open Variation Database DB-ID BRCA2_001800, 33629534, 34657357, 34645131). This variant has been identified in 1/244054 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	RCV000168232	SCV000694563	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1796_1800delCTTAT (p.Ser599X) 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 allele was found at a frequency of 4.1e-06 in 244054 control chromosomes. c.1796_1800delCTTAT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Kim_2012, Lang_2017, Palmer_2020). 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. 13 clinical diagnostic laboratories 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031337	SCV000839921	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-25	criteria provided, single submitter	clinical testing	The c.1796_1800del (p.Ser599*) variant in the BRCA2 gene has been detected multiple patients with breast cancer [reported as 2022del5 in PMID 8988179]. This variant creates a premature stop codon at amino acid position 599 of the BRCA2 protein. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant thus classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000043887	SCV000887761	pathogenic	not provided	2021-09-24	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 and families affected with breast/ovarian cancer in the published literature (PMID: 8988179 (1997), 22798144 (2012), 25371446 (2014), 29084914 (2018), 29335925 (2018)). Based on the available information, this variant is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000043887	SCV001447156	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Cancer Genomics Laboratory, City of Hope Comprehensive Cancer Center	RCV000031337	SCV001739442	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-01-01	criteria provided, single submitter	clinical testing
Laan Lab, Human Genetics Research Group, University of Tartu	RCV000031337	SCV002538624	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV002490434	SCV002804078	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	2021-07-14	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000031337	SCV003807161	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-12-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV000031337	SCV004037368	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-12-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460499	SCV004216147	pathogenic	Familial cancer of breast	2023-05-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532433	SCV004711871	pathogenic	BRCA2-related disorder	2024-02-14	criteria provided, single submitter	clinical testing	The BRCA2 c.1796_1800del5 variant is predicted to result in premature protein termination (p.Ser599*). This variant has been reported to be causative for breast or ovarian cancer (described as c.2022del5, Gayther et al 1997. PubMed ID: 8988179; Azzollini. 2016. PubMed ID: 27062684 ; Table S2, Fostira. 2018. PubMed ID: 29335925). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37756/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168232	SCV004848363	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-19	criteria provided, single submitter	clinical testing	The p.Ser599X variant (also reported as c.2022del5, c.2024_2028delCTTAT, and c.2024del5) in BRCA2 has been reported in the literature in >15 individuals with BRCA2-related cancers and segregated with disease in at least three relatives (Gayther 1997, Håkansson 1997, Loman 2001, Ladopoulou 2002, Armakolas 2002, Bonadona 2005, Tommasi 2008, Kim 2012, Castéra 2014, Torres-Mejía 2015, Azzollini 2016, Barnes-Kedar 2018, Fostira 2018, Palmero 2018,Singh 2018,Bhaskaran 2019). This vairant has been identified in 1/111114 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 599, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282361.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1; PM2; PS4, PP1.
Sharing Clinical Reports Project (SCRP)	RCV000031337	SCV000053942	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-05-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031337	SCV000145940	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353530	SCV000591768	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ser599X variant was identified in 2 of 816 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancer (Gayther 1997, Bayraktar 2012). The variant was also identified in dbSNP (ID: rs276174813) “With pathogenic allele”, HGMD, the ClinVar database (classified as a pathogenic variant by the BIC and Invitae), GeneInsight VariantWire database (1X, classified as “pathogenic” by a clinical laboratory), the BIC database (12X with clinical importance) and UMD (15X as a causal variant). The p.Ser599X variant leads to a premature stop codon at position 599, which is predicted to lead to 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000043887	SCV001905987	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000043887	SCV001930456	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031337	SCV004244231	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing