Submissions for variant NM_000059.4(BRCA2):c.5645C>A (p.Ser1882Ter)

gnomAD frequency: 0.00002  dbSNP: rs80358785

Total submissions: 45

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031565	SCV000282410	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167830	SCV000072718	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1882*) 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 (rs80358785, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian and prostate cancer (PMID: 15024741, 21952622, 22144684, 22535016, 22666503). This variant is also known as 5873C>A. ClinVar contains an entry for this variant (Variation ID: 37984). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131114	SCV000186044	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The p.S1882* pathogenic mutation (also known as c.5645C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 5645. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been reported in an individual diagnosed with triple negative breast cancer at age 37 (Meyer P et al. PLoS One. 2012 May;7:e38361), in two individuals with ovarian cancer (Sakomoto I et al. Cancer. 2016 Jan;122:84-90), and in a family with multiple cases of breast cancer (Verhoog LC et al. J. Clin. Oncol. 1999 Nov;17:3396-402). In another study, this alteration was reported as an Eastern European founder mutation (Caputo S et al. Nucleic Acids Res. 2012 Jan;40:D992-1002). This mutation has also been detected in a cohort of affected patients meeting genetic testing criteria for HBOC (Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238), a cohort of patients with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53), as well as in multiple cohorts of unselected breast cancer patients (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in 7 members of one family (Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3). 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	RCV000044705	SCV000210359	pathogenic	not provided	2021-01-19	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 a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25682074, 30287823, 30430080, 29339979, 29446198, 30093976, 31263054, 15689453, 10660329, 22144684, 22535016, 22666503, 21952622, 22009639, 26439132, 26221963, 26064523, 25863477, 25802882, 27225637, 25525159, 24916970, 24249303, 27533253, 27836010, 26733283, 27271530, 27767231, 15131399, 26848529, 27433846, 28283652, 28324225, 28259476, 29084914, 28724667, 28993434, 28715532, 29215753, 29659587, 29346284, 30274973, 30078507, 30720243, 30702160, 30322717, 27257965, 32467295, 11597388, 32318955, 31447099, 32853339, 32341426, 31825140, 32710294, 30875412, 33608381, 30787465, 31742824)
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240722	SCV000265907	pathogenic	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031565	SCV000327251	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044705	SCV000600653	pathogenic	not provided	2021-08-07	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with breast or prostate cancer in the published literature (PMID: 33918338 (2020), 27433846 (2016) and 22666503 (2012)). Based on the available information, this variant is classified as pathogenic.
Department of Medical Genetics, Oslo University Hospital	RCV000031565	SCV000605680	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131114	SCV000683721	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 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 12 individuals affected with breast and/or ovarian cancer (PMID: 15024741, 15689453, 20104584, 22535016, 22666503, 26439132, 27257965, 28039656, 28724667, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_000141) and four individuals affected with prostate cancer (PMID: 27433846, 31214711). This variant also has been reported in two siblings who were compound heterozygous carriers with a second pathogenic BRCA2 variant and were both affected with Wilms tumor (PMID: 15689453). This variant has been identified in 4/249416 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.
GeneKor MSA	RCV000585709	SCV000693572	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single amino acid change from Serine to a Termination codon at amino acid residue 1882 of the BRCA2 gene. It is expected to result in a truncated, non-functional protein. Truncating variants in the BRCA2 gene are known to be pathogenic. This variant is also known as 5873C>A in the literature and has been described in patients and families with breast, ovarian and prostate cancer (PMID: 22144684, 22535016, 22666503, 21952622, 15024741). The mutation database ClinVar contains entries for this variant (Variation ID: 37984).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167830	SCV000694888	pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-31	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.5645C>A (p.Ser1882X) 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. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/120628 (1/40160, 0.0000249), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333 (0.0007503). In addition, it needs to be noted that these three occurrences need to be cautiously considered due to the fact that the ExAC cohort contains individuals that could harbor a BRCA2 phenotype. However, multiple affected individuals have been reported via publications, along with numerous reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031565	SCV000743309	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	RCV000031565	SCV000744472	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735569	SCV000902206	pathogenic	Breast and/or ovarian cancer	2017-03-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167830	SCV000967739	pathogenic	Hereditary breast ovarian cancer syndrome	2018-01-17	criteria provided, single submitter	clinical testing	The p.Ser1882X variant in BRCA2 has been reported in >60 individuals with BRCA2- associated cancers and segregated with disease in 2 affected relatives from 2 fa milies (Caputo 2012, De Silva 2017, Heidemann2012, Rebbeck 2016, Reid 2005). Thi s variant has also been identified in 1/17202 East Asian and 2/110946 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs80358785). This nonsense variant leads to a premature terminati on codon at position 1882, which is predicted to lead to a truncated or absent p rotein. Heterozygous loss of function of the BRCA2 gene is an established diseas e mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this va riant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENI GMA expert panel (ClinVar SCV000282410.1). In summary, this variant meets criter ia to be classified as pathogenic for HBOC in an autosomal dominant manner based upon predicted impact to the protein, absence in the general population and pre sence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1; PS4; PM 2 (Richards 2015).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002489	SCV001160441	pathogenic	not specified	2019-03-26	criteria provided, single submitter	clinical testing	The BRCA2 c.5645C>A; p.Ser1882Ter variant (rs80358785), also known as 5873C>A, is reported in several individuals with hereditary breast and ovarian cancer syndrome and is described as a founder mutation in the Eastern European population (Caputo 2012, Heramb 2018, Meisel 2017, Momozawa 2018). It has also been reported in two brothers with Wilms tumor and brain tumors, who also carry an additional truncating variant in trans (Reid 2005). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37984). It is found in the general population with a low overall allele frequency of 0.002% (4/249416 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Meisel C et al. Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. Arch Gynecol Obstet. 2017 May;295(5):1227-1238. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Reid S et al. Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet. 2005 Feb;42(2):147-51.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031565	SCV001434851	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-02-21	criteria provided, single submitter	clinical testing	The c.5645C>A (p.Ser1882*) variant in the BRCA2 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple families affected with Hereditary Breast and Ovarian Cancer (PMID 10550133, 22144684, 28324225) and has also been reported in individuals affected with triple negative breast cancer (PMID 22666503), ovarian cancer (PMID 26439132) or metastatic prostate cancer (PMID 27433846). This variant is extremely rare in general population. Therefore, this c.5645C>A (p.Ser1882*) variant in the BRCA2 gene is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000044705	SCV001450433	pathogenic	not provided	2019-09-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000044705	SCV001501472	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV001799612	SCV002044439	pathogenic	Breast carcinoma	2021-12-10	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4, PM2_SUP
Research Institute, Aichi Cancer Center	RCV000167830	SCV002503893	pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131114	SCV002536157	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496484	SCV002809692	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	2022-04-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000044705	SCV003810499	pathogenic	not provided	2022-12-05	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000044705	SCV004026115	pathogenic	not provided	2022-07-29	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2_SUP
Baylor Genetics	RCV000585709	SCV004211865	pathogenic	Familial cancer of breast	2024-01-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031565	SCV004846612	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-10	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 12 individuals affected with breast and/or ovarian cancer (PMID: 15024741, 15689453, 20104584, 22535016, 22666503, 26439132, 27257965, 28039656, 28724667, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_000141) and four individuals affected with prostate cancer (PMID: 27433846, 31214711). This variant also has been reported in two siblings who were compound heterozygous carriers with a second pathogenic BRCA2 variant and were both affected with Wilms tumor (PMID: 15689453). This variant has been identified in 4/249416 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000044705	SCV005199793	pathogenic	not provided	2023-10-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000585709	SCV005368118	pathogenic	Familial cancer of breast	2024-04-29	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
Sharing Clinical Reports Project (SCRP)	RCV000031565	SCV000054170	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-08-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031565	SCV000146653	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000031565	SCV000212022	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000167830	SCV000587784	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031565	SCV000733269	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735569	SCV000863707	pathogenic	Breast and/or ovarian cancer	2004-02-13	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785224	SCV000923792	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
CZECANCA consortium	RCV000735569	SCV001451859	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Rudy L. Ruggles Biomedical Research Institute, Danbury Hospital	RCV001281099	SCV001451935	pathogenic	Malignant tumor of prostate; Metastatic Prostate Small Cell Carcinoma	2020-04-15	no assertion criteria provided	research	This BRCA2 variant (rs80358785) has been found in 65 year-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000044705	SCV001552752	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000044705	SCV001906448	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000044705	SCV001952938	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV000585709	SCV002520807	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
Laboratory for Genotyping Development, RIKEN	RCV003162274	SCV002758323	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003483439	SCV004228895	not provided	BRCA2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-19-2017 by Lab Myriad Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
BRCAlab, Lund University	RCV000031565	SCV004243679	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing