Submissions for variant NM_000059.4(BRCA2):c.3599_3600del (p.Asp1199_Cys1200insTer)

dbSNP: rs80359391

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113196	SCV000300648	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	RCV000195400	SCV000072243	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1200*) 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 (rs80359391, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 15645491, 16683254, 24504028, 24728189, 25863477). This variant is also known as 3827delGT. ClinVar contains an entry for this variant (Variation ID: 51493). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000044230	SCV000210737	pathogenic	not provided	2022-11-28	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 individuals with BRCA2-related cancers (De Leon Matsuda et al., 2002; Liede et al., 2002; Song et al., 2014; Kang et al., 2015; Nielsen et al., 2016); 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 3827delGT; This variant is associated with the following publications: (PMID: 26833046, 32455662, 32980694, 31492746, 29922827, 34697415, 11920621, 12442265, 22798144, 24728189, 24504028, 26287763, 25863477, 26681312, 28166811, 27767231, 28617445, 29128982, 29348823, 29470806, 29446198, 30309222, 30287823, 30720243, 30702160, 30322717, 30972954, 31263054, 29176636, 33646313, 33372952, 33151324, 30787465, 31742824, 33087929, 34645131, 15645491)
Ambry Genetics	RCV000162919	SCV000213406	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-19	criteria provided, single submitter	clinical testing	The c.3599_3600delGT pathogenic mutation (also known as p.C1200*), located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at positions 3599 to 3600. This changes the amino acid from a cysteine to a stop codon within coding exon 10. This mutation has been reported in multiple individuals diagnosed with breast or ovarian cancer (De Leon Matsuda ML et al. Int. J. Cancer. 2002 Apr;98:596-603; Hamann U et al. Eur. J. Hum. Genet. 2003 Jun;11:464-7; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Kang E et al. Breast Cancer Res Treat. 2015 May;151:157-68; Hirasawa A et al. Oncotarget. 2017 Dec;8:112258-112267; Kwon BS et al. Cancer Res Treat. 2018 Oct; Lovejoy LA et al. Austin J Cancer Clin Res. 2018 Jun; 5(1):1082; Bhaskaran SP et al. Int J Cancer. 2019 Jan). This mutation has also been reported in a child with biallelic BRCA2 related Fanconi Anemia who was diagnosed with leukemia by the age of 2 years (Meyer S et al. Genes Chromosomes Cancer. 2005 Apr;42:404-15). Of note, this alteration is also designated as 3827delGT 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113196	SCV000326886	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000113196	SCV000488173	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044230	SCV000600557	pathogenic	not provided	2020-10-16	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in symptomatic individuals with breast and/or ovarian cancer and a boy with a phenotype of Fanconi Anemia in the published literature (PMIDs: 22798144 (2012), 24259538 (2014), 24728189 (2014), 26287763 (2015), 29348823 (2017), 30309222 (2019), and 30702160 (2019)). Based on the available information, this variant is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113196	SCV000743287	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162919	SCV000903412	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 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 10 individuals affected with breast and/or ovarian cancer (PMID: 11920621, 12774040, 20104584, 22798144, 24504028, 24728189, 26287763, 29348823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001069) and 2 individuals affected with prostate cancer (PMID: 31214711). This variant has been detected in a compound heterozygous carrier affected with Fanconi anemia (PMID: 15645491). This variant also has been detected in unaffected individuals (PMID: 11920621, 30287823, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_001069) and in 4/251042 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	RCV000195400	SCV000916858	pathogenic	Hereditary breast ovarian cancer syndrome	2021-02-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3599_3600delGT (p.Cys1200X) 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 1.6e-05 in 254218 control chromosomes. c.3599_3600delGT has been widely 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 and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000044230	SCV001449553	pathogenic	not provided	2019-10-21	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310145	SCV001499723	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113196	SCV003932719	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A known pathogenic variant was detected in the BRCA2 gene (p.Cys1200Ter). This sequence change creates a premature translational stop signal (p.Cys1200*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 24504028, 16683254, 25863477, 15645491, 24728189). This variant is also known as 3827delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 51493) with 16 submissions, all pathogenic, 3 stars, no conflict, and reviewed by an expert panel. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044230	SCV004027418	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460572	SCV004216156	pathogenic	Familial cancer of breast	2023-11-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195400	SCV004847918	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Cys1200X variant in BRCA2 (resulting from c.3599_3600delGT) has been reported in at least 13 individuals with BRCA2-related cancers (De Leon Matsuda 2002, Cunningham 2014, Susswein 2016, Hirasawa 2017, Momozawa 2018, BIC database). It has also been identified in 1/18394 East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This frameshift variant is predicted to lead to a premature termination codon at position 1200. 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 Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51493). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000113196	SCV005046019	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000044230	SCV005375362	pathogenic	not provided		criteria provided, single submitter	not provided
All of Us Research Program, National Institutes of Health	RCV004803164	SCV005424387	pathogenic	BRCA2-related cancer predisposition	2024-09-28	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 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 10 individuals affected with breast and/or ovarian cancer (PMID: 11920621, 12774040, 20104584, 22798144, 24504028, 24728189, 26287763, 29348823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001069) and 2 individuals affected with prostate cancer (PMID: 31214711). This variant has been detected in a compound heterozygous carrier affected with Fanconi anemia (PMID: 15645491). This variant also has been detected in unaffected individuals (PMID: 11920621, 30287823, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_001069) and in 4/251042 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.
Fulgent Genetics, Fulgent Genetics	RCV005007966	SCV005633903	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-03-20	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113196	SCV000146265	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	RCV000195400	SCV000587675	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000113196	SCV000591871	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Cys1200X variant was identified by De Leon Matsuda (2002) in one individual with breast cancer and in one control subject with a “suspicious breast mass” which was interpreted as fibrocystic disease, though a biopsy was not taken from the control subject. The variant was also identified in dbSNP (ID: rs80359391), HGMD, and UMD (3X as a causal variant). The p.Cys1200X variant leads to a premature stop codon at position 1200, 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000044230	SCV000778665	pathogenic	not provided	2017-11-30	no assertion criteria provided	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257548	SCV001434374	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000044230	SCV001906290	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000044230	SCV001964947	pathogenic	not provided		no assertion criteria provided	clinical testing
Integrative Tumor Epidemiology Branch, National Institutes of Health	RCV002266917	SCV002549692	pathogenic	Chordoma	2021-03-22	no assertion criteria provided	research
BRCAlab, Lund University	RCV000113196	SCV002588864	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162372	SCV002758420	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732610	SCV005363471	pathogenic	BRCA2-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The BRCA2 c.3599_3600delGT variant is predicted to result in premature protein termination (p.Cys1200*). This variant has been associated with breast cancer, ovarian cancer and severe Fanconi anemia (reported as 3827delGT in De Leon Matsuda et al. 2002. PubMed ID: 11920621; Arai et al. 2018. PubMed ID: 29176636; Hirasawa et al. 2017. PubMed ID: 29348823; Petridis et al. 2019. PubMed ID: 31263054; van der Hout et al. 2006. PubMed ID: 16683254; Meyer et al. 2005. PubMed ID: 15645491). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51493/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.