Submissions for variant NM_000059.4(BRCA2):c.5857G>T (p.Glu1953Ter)

gnomAD frequency: 0.00001  dbSNP: rs80358814

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077363	SCV000300944	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	RCV000195356	SCV000072788	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.Glu1953*) 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 (rs80358814, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 9150172, 9792861, 15382066, 16683254, 23318356, 23621881, 28008555). It is commonly reported in individuals of French Canadian ancestry (PMID: 9150172, 9792861, 15382066, 16683254, 23318356, 23621881, 28008555). This variant is also known as 6085G>T. ClinVar contains an entry for this variant (Variation ID: 51952). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131117	SCV000186047	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-08	criteria provided, single submitter	clinical testing	The p.E1953* pathogenic mutation (also known as c.5857G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5857. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This pathogenic mutation is considered a founder mutation in the French Canadian population and has been detected in numerous hereditary breast and/or ovarian cancer families to date (Phelan CM et al. Nat. Genet. 1996 May;13(1):120-2; Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May;60(5):1236-9; Frank TS et al. J. Clin. Oncol. 1998 Jul;16(7):2417-25; Oros KK et al. Int. J. Cancer. 2004 Nov;112(3):411-9; Cavallone L et al. Fam. Cancer. 2010 Dec;9(4):507-17; Taherian N et al. Nat Rev Urol. 2013 Feb;10(2):116-22; Ghadirian P et al. Clin. Genet. 2014 Jan;85(1):31-5; Fernandes GC et al. Oncotarget. 2016 Dec;7(49):80465-80481). Of note, this alteration is also designated as 6085G>T 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	RCV000044775	SCV000210373	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; French Canadian pathogenic founder variant observed in multiple families with breast, ovarian, and prostate cancer (Serova-Sinilnikova 1997, Frank 1998, Tonin 1998, Oros 2004, Zhang 2011, Taherian 2013, Belanger 2015); 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; Also known as 6085G>T; This variant is associated with the following publications: (PMID: 25525159, 21324516, 25884701, 7478555, 9667259, 23621881, 23199084, 32772980, 32300229, 9150172, 23318356, 26425718, 9792861, 19863560, 15382066, 17386038, 20694749, 28715532, 28503720, 16905680, 27741520, 26786923, 29907814, 29446198, 30274973, 30720243, 32885271, 32338768, 30787465, 31360904)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000195356	SCV000219366	pathogenic	Hereditary breast ovarian cancer syndrome	2017-03-08	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077363	SCV000267789	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195356	SCV000271331	pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-30	criteria provided, single submitter	clinical testing	The p.Glu1953X variant in BRCA2 has been reported in numerous individuals with BRCA2-associated cancers and segregated with disease in 4 affected individuals from one family (Phelan 1996 PMID: 8673090; Serova-Sinilnikova 1997 PMID: 9150172; Ghadirian 2009 PMID: 19863560; Taherian 2013 PMID: 233108356; Ghadirian 2014 PMID: 23621881; Fernandes 2016 PMID: 27741520; Bannon 2018 PMID: 30274973; Pritzlaff 2017 PMID: 28008555; Breast Cancer Information Core (BIC) database; https://research.nhgri.nih.gov/bic/)). It has also been identified in 0.002% (2/113514) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 1953, 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 HBOC. Additionally, this variant was classified as pathogenic on Sept. 13, 2016, by the ClinGen-approved ENIGMA expert panel (SCV000300944.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting, PP1.
Color Diagnostics, LLC DBA Color Health	RCV000131117	SCV000292172	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-30	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 individuals with a personal or family history of prostate, breast, and/or ovarian cancer (PMID: 9150172, 9792861, 15382066, 16683254, 19863560, 23318356, 23621881, 28008555, 29446198, 33471991). This variant has been identified in 2/250950 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077363	SCV000327300	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000313209	SCV000383727	pathogenic	BRCA2-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	The BRCA2 c.5857G>T (p.Glu1953Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Glu1953Ter variant has been reported in at least seven studies in individuals with breast, ovarian or prostate cancer in which it is found in a heterozygous state in at least 44 patients. The variant is a common cause of breast and ovarian cancer in the French Canadian population (Serova-Sinilnikova et al. 1997; Tonin et al. 1998; Oros et al. 2004; van der Hout et al. 2006; Cavallone et al. 2010; Taherian et al. 2014; Ghadirian et al. 2014). Control data are unavailable from these studies for this variant, which is reported at a frequency of 0.00001 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Although the p.Glu1953Ter variant has not been reported in any cases of Fanconi anemia, it is generally accepted that pathogenic variants in the BRCA2 gene also confer carrier status for Fanconi anemia. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Glu1953Ter variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Department of Pathology and Molecular Medicine, Queen's University	RCV000195356	SCV000588104	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515293	SCV000611179	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; Tracheoesophageal fistula	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195356	SCV000694907	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5857G>T (p.Glu1953X) 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 8e-06 in 250950 control chromosomes. c.5857G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Frank_1998, Ghadirian_2014, Oros_2004, Serova-Sinilnikova_1997). 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. Fifteen 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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077363	SCV000744478	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044775	SCV000889081	pathogenic	not provided	2022-08-07	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/250950 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, this variant has been described in individuals/families with breast/ovarian cancer (PMIDs: 33471991 (2021), 32885271 (2021), 32772980 (2020), 28503720 (2017), 28008555 (2017), 27741520 (2016), 21324516 (2011), 20694749 (2010), 17148771 (2006), 9667259 (1998), 9792861 (1998), and 8673090 (1996)) and described as a common French-Canadian founder variant (PMIDs: 25884701 (2015), 23621881 (2014), 15382066 (2004), 11307153 (2001), and 9792861 (1998)). This variant has also been reported in individuals with prostate cancer (PMIDs: 23318356 (2013) and 32338768 (2020)) and pancreatic cancer (PMID: 30274973 (2018)). Based on the available information, this variant is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735575	SCV000902208	pathogenic	Breast and/or ovarian cancer	2023-05-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000044775	SCV001160340	pathogenic	not provided	2022-10-19	criteria provided, single submitter	clinical testing	The BRCA2 c.5857G>T; p.Glu1953Ter variant (rs80358814), also reported as 6085G>T, has been described in multiple individuals affected with hereditary breast and ovarian cancer (HBOC), including prostate and male breast cancers (Pritzlaff 2017, Serova-Sinilnikova 1997, Taherian 2013, Tonin 1998, van der Hout 2006) and is a common cause of HBOC in the French Canadian population (Ghadirian 2014, Oros 2004). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51952) and is observed on only 2 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. 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 pathogenic. REFERENCES Ghadirian P et al. Screening for BRCA1 and BRCA2 mutations among French-Canadian breast cancer cases attending an outpatient clinic in Montreal. Clin Genet. 2014 Jan;85(1):31-5. PMID: 23621881. Oros K et al. Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5 BRCA1 and BRCA2 mutations. Int J Cancer. 2004 Nov 10;112(3):411-9. PMID: 15382066. Pritzlaff M et al. Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast Cancer Res Treat. 2017 Feb;161(3):575-586. PMID: 28008555. Serova-Sinilnikova O et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997 May;60(5):1236-9. PMID: 9150172. Taherian N et al. Familial prostate cancer: the damage done and lessons learnt. Nat Rev Urol. 2013 Feb;10(2):116-22. PMID: 23318356. Tonin P et al. Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet. 1998 Nov;63(5):1341-51. PMID: 9792861. van der Hout A et al. A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. Hum Mutat. 2006 Jul;27(7):654-66. PMID: 16683254
CeGaT Center for Human Genetics Tuebingen	RCV000044775	SCV002063093	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001843467	SCV002103012	pathogenic	Familial cancer of breast	2021-03-23	criteria provided, single submitter	clinical testing	Incidental finding in clinical exome sequencing. PVS1, PS1
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000077363	SCV002103023	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-03-23	criteria provided, single submitter	clinical testing	Incidental finding in clinical exome sequencing. PVS1, PS1
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001843469	SCV002103034	pathogenic	Malignant tumor of prostate	2021-03-23	criteria provided, single submitter	clinical testing	Incidental finding in clinical exome sequencing. PVS1, PS1
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001843470	SCV002103045	pathogenic	Medulloblastoma	2021-03-23	criteria provided, single submitter	clinical testing	Incidental finding in clinical exome sequencing. PVS1, PS1
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001843468	SCV002103056	pathogenic	Wilms tumor 1	2021-03-23	criteria provided, single submitter	clinical testing	Incidental finding in clinical exome sequencing. PVS1, PS1
Baylor Genetics	RCV001843467	SCV004213634	pathogenic	Familial cancer of breast	2023-08-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077363	SCV004846656	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-09	criteria provided, single submitter	clinical testing	The c.5857G>T (p.Glu1953*) variant in the BRCA2 gene is located on the exon 11 and is predicted to introduce a premature translation termination codon (p.Glu1953*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/pancreatic cancer and it is one of the frequently reported variants in French Canadian population (PMID: 34298626, 28503720, 35949895, 35714671, 26425718, 32772980). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 51952) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (2/250950). Therefore, the c.5857G>T (p.Glu1953*) variant of BRCA2 has been classified as pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000077363	SCV005045905	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000044775	SCV005199795	pathogenic	not provided	2023-07-03	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077363	SCV000109160	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077363	SCV000146715	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	RCV000195356	SCV000587805	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353570	SCV000592006	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu1953X variant was identified in 28 of 10010 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian, and prostate cancer, and it was present in 1 of 3994 control chromosomes (frequency: 0.0002) from healthy individuals (Belanger 2015, Cavallone 2010, Ghadirian 2009, Janavicius 2010, Lubinski 2004, Serova-Sinilnikova 1997, Taherian 2013, Thompson 2016, Tonin 2001, Zhang 2011). The variant was also identified in dbSNP (ID: rs80358814) as “With Pathogenic allele”, ARUP Laboratories BRCA Mutations Database (classified as definitely pathogenic), the ClinVar database (classified as pathogenic 16x including by ENIGMA, Invitae, Ambry Genetics, and GeneDx), the BIC database (32x with clinical importance), UMD (6x with a “causal” classification). The variant was also identified in control databases including the Genome Aggregation Consortium database in 3 of 246032 chromosomes (freq. 0.00001) in the following populations: European in 3 of 111544 chromosomes (freq. 0.00003). The variant was also identified by our laboratory in 5 individuals with breast and pancreatic cancer. The variant described in the literature as a French-Canadian founder mutation (Belanger 2015, Cavallone 2010, Ghadirian 2009, Janavicius 2010, Lubinski 2004, Tonin 2001). The variant has also been described in a Brazilian population (Fernandes 2016). In addition, one case study suggests the variant lead to early-onset and aggressive prostate cancer (Taherian 2013). The p.Glu1953X variant leads to a premature stop codon at position 1953, 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077363	SCV000733274	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735575	SCV000863713	pathogenic	Breast and/or ovarian cancer	2015-10-28	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000044775	SCV001906240	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000044775	SCV002033928	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077363	SCV004243691	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000313209	SCV005354129	pathogenic	BRCA2-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The BRCA2 c.5857G>T variant is predicted to result in premature protein termination (p.Glu1953*). In the literature, this variant is also referred to as c.6085G>T. This variant has been reported in multiple individuals with hereditary breast and ovarian cancer (HBOC) and prostate cancer (Serova-Sinilnikova et al. 1997. PubMed ID: 9150172; Tonin et al. 1998. PubMed ID: 9792861; van der Hout et al. 2006. PubMed ID: 16683254; Taherian et al. 2013. PubMed ID: 23318356; Pritzlaff et al. 2017. PubMed ID: 28008555). Of note, the c.5857G>T (p.Glu1953*) variant is a common cause of HBOC in the French Canadian population (Tonin et al. 1998. PubMed ID: 9792861; Tonin et al. 2001. PubMed ID: 11307153; Oros et al. 2004. PubMed ID: 15382066). This variant is reported in 0.0018% 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/51952/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.