Submissions for variant NM_000059.4(BRCA2):c.5682C>G (p.Tyr1894Ter)

dbSNP: rs41293497

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)	RCV000031570	SCV000282412	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	RCV000044719	SCV000072732	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1894*) 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 (rs41293497, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer, breast cancer, prostate cancer, and Fanconi anemia (PMID: 11179017, 15070707, 16168118, 18042939, 20736950). This variant is also known as 5910C>G. ClinVar contains an entry for this variant (Variation ID: 37989). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131121	SCV000186051	pathogenic	Hereditary cancer-predisposing syndrome	2025-02-15	criteria provided, single submitter	clinical testing	The p.Y1894* pathogenic mutation (also known as c.5682C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5682. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) cohorts (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Marroni F et al. Eur J Hum Genet, 2004 Nov;12:899-906; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Tea MK et al. Maturitas, 2014 Jan;77:68-72; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Lang GT et al. Int. J. Cancer 2017 Jul;141(1):129-142; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Alemar B et al. PLoS One, 2017 Nov;12:e0187630; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Wu H et al. Hum Hered, 2019 Feb;84:160-169; Cao WM et al. BMC Cancer, 2019 Jun;19:551; Guo X et al. Int J Cancer, 2020 04;146:2175-2181; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Liu Y et al. J Hematol Oncol, 2021 01;14:18; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), including patients with male breast cancer (Tai YC et al. J Natl Cancer Inst, 2007 Dec;99:1811-4). This mutation has also been reported in individuals with prostate, pancreatic, colorectal and gastric cancers (Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; AlDubayan SH et al. Am J Hum Genet, 2018 03;102:401-414; Dudley B et al. Cancer, 2018 04;124:1691-1700; Wei Y et al. Oncologist, 2020 07;25:e1042-e1050; Zhou J et al. Oncology, 2020 Jun;98:583-588), as well as in members of one Fanconi anemia family (Wagner JE et al. Blood, 2004 Apr;103:3226-9). 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	RCV000160095	SCV000210363	pathogenic	not provided	2023-01-20	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; Identified in individuals with a personal or family history consistent with pathogenic variants in this gene (Risch et al., 2001; Pohlreich et al., 2005; Edwards et al., 2010; Cini et al., 2016; Fernandes et al., 2016; Kim et al., 2016; Dudley et al., 2018); 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 5910C>G; This variant is associated with the following publications: (PMID: 20736950, 29446198, 29339979, 29360161, 32211327, 29922827, 28888541, 24055113, 25525159, 11897832, 11179017, 27003155, 24156927, 26852015, 25637381, 26852130, 26219728, 25682074, 26848529, 27225637, 27741520, 27836010, 28176296, 28294317, 27356891, 28724667, 28423363, 29478780, 29907814, 29909963, 16168118, 29161300, 30720243, 19471317, 17972171, 18042939, 15340362, 15070707, 31174498, 31528241, 20104584, 30702160, 32467295, 34399810, 11597388, 32318955, 32521533, 31447099, 32101877, 31825140, 32885271, 30787465, 33087929, 33804961)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160095	SCV000296756	pathogenic	not provided	2023-04-13	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, 0.000004 (1/250362 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with breast cancer (PMID: 18042939 (2007), 28724667 (2017), 29907814 (2018), 31174498 (2019), 32029870 (2020)), ovarian cancer (PMID: 1179017 (2001)), prostate cancer (PMID: 20736950 (2010)), gastric cancer (PMID: 32521533 (2020)), and liver cancer (PMID: 34399810 (2021)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031570	SCV000327264	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044719	SCV000494385	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.5682C>G (p.Tyr1894X) 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.6644_6647delACTC, c.6682dupG, c.6997_6998delGT, etc.). This variant is absent in 120576 control chromosomes from ExAC. This variant is a recurrent pathogenic mutation found in several HBOC patients/families and in individuals undergoing BRCA1/2 clinical testing. In compound heterozygous with another variant, it has also been reported to cause Fanconi Anemia. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as a Disease Variant (or Pathogenic).
Fulgent Genetics, Fulgent Genetics	RCV002477037	SCV000575740	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	2021-10-11	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000044719	SCV000586962	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000044719	SCV000588102	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031570	SCV000605682	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515199	SCV000611178	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; Esophageal atresia/tracheoesophageal fistula	2017-05-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000031570	SCV000677688	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131121	SCV000683723	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-16	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 18 individuals affected with breast and/or ovarian cancer (PMID: 11179017, 16168118, 18042939, 17972171, 20104584, 25682074, 25927356, 26219728, 26687385, 27741520, 28294317, 28724667, 28831036, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001092): and in individuals affected with pancreatic, prostate and colorectal cancer (PMID: 20736950, 29360161, 29478780). This variant also has been reported in related individuals affected with Fanconi anemia (PMID: 15070707). This variant has been identified in 1/250362 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031570	SCV000743310	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	RCV000031570	SCV000744473	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Academic Department of Medical Genetics, University of Cambridge	RCV000131121	SCV000992212	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000160095	SCV001248278	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031570	SCV001428738	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-01-28	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000160095	SCV001447347	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735572	SCV002043214	pathogenic	Breast and/or ovarian cancer	2023-02-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131121	SCV002536161	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000031570	SCV002580247	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-09-02	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000031570	SCV002587022	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-09-07	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000160095	SCV003814981	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031570	SCV004041501	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-01-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002250489	SCV004213726	pathogenic	Familial cancer of breast	2024-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003493419	SCV004242421	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-15	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
All of Us Research Program, National Institutes of Health	RCV000031570	SCV004846623	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	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 18 individuals affected with breast and/or ovarian cancer (PMID: 11179017, 16168118, 18042939, 17972171, 20104584, 25682074, 25927356, 26219728, 26687385, 27741520, 28294317, 28724667, 28831036, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001092): and in individuals affected with pancreatic, prostate and colorectal cancer (PMID: 20736950, 29360161, 29478780). This variant also has been reported in related individuals affected with Fanconi anemia (PMID: 15070707). This variant has been identified in 1/250362 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044719	SCV004848272	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Tyr1894X (c.5682C>G) variant in BRCA2 has been reported in >20 individuals with BRCA2-related cancers (Risch 2001, Edwards 2010, Tea 2014, Alemar 2017, AlDubayan 2018, Dudley 2018, BIC database). Furthermore, another variant at this position resulting in the same amino acid change (c.5681dup, p.Tyr1894X) is classified as pathogenic for hereditary breast and ovarian cancer (HBOC) by our laboratory. The c.5682C>G variant has also been identified in 0.001% (1/113148) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. This nonsense variant is predicted to lead to a premature termination codon at position 1894, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in HBOC. Finally, the p.Tyr1894X (c.5682C>G) variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37989). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4, PS1.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000044719	SCV005045779	pathogenic	Hereditary breast ovarian cancer syndrome	2018-08-13	criteria provided, single submitter	clinical testing	The c.5682C>G (p.Tyr1894*) variant in the BRCA2 gene is located on the exon 11 and is predicted to introduce a premature translation termination codon (p.Tyr1894*), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832). This variant has been reported in more than 10 unrelated individuals with breast or ovarian cancer (PMID: 35912179, 31528241, 26852015, 31837001, 33113089, 36119527). This variant is reported in ClinVar as pathogenic (ID: 37989) and reviewed by the expert panel. This variant is rare in the general population according to gnomAD (1/250362). Therefore, the c.5682C>G (p.Tyr1894*) variant of BRCA2 has been classified as pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031570	SCV005045902	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Mayo Clinic Laboratories, Mayo Clinic	RCV000160095	SCV005414154	pathogenic	not provided	2024-08-08	criteria provided, single submitter	clinical testing	PM3, PM5_strong, PVS1
NHS Central & South Genomic Laboratory Hub	RCV005252701	SCV005907153	pathogenic	Inherited breast cancer and ovarian cancer	2025-04-09	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031570	SCV000054175	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031570	SCV000146669	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148424	SCV000190123	pathogenic	Ovarian cancer	2014-06-01	no assertion criteria provided	research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044719	SCV000587792	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000160095	SCV000591987	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Tyr1894* variant was identified in 18 of 8970 proband chromosomes (frequency: 0.002) from Chinese, Italian, and Czech individuals or families with breast, ovarian and prostate cancers and was not identified in 182 control chromosomes from healthy individuals (Cini 2016, Cao WM, Risch 2001, Edwards 2010, Pohlreich 2005, Borg 2010, Caux-Moncoutier 2009). The variant was also identified in dbSNP (ID: rs41293497) as “With Likely benign, Pathogenic allele”, and in the NHLBI GO Exome Sequencing Project in 1 of 8596 European American alleles (frequency: 0.0001). The variant was identified in ClinVar (classified as pathogenic by ENIGMA, GeneDX, Invitae, Ambry Genetics, and five other submitters). In addition, the variant was identified as pathogenic in the COGR database by Women’s College Hospital, Children’s’ Hospital of Eastern Ontario, Kingston General Hospital – Queen’s University and North York General Hospital. The variant was also identified by our laboratory in three individuals with breast and basal cell carcinomas, in the BIC database (67x as Class 5 with clinical importance), and in the ARUP Laboratories BRCA Mutations Database (as definitely pathogenic). The variant was not identified in COSMIC, the Fanconi Anemia Mutation Database (LOVD), the 1000 Genomes Project, or the Exome Aggregation Consortium database (August 8, 2016). The p.Tyr1894* variant leads to a premature stop codon at position 1894, 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	RCV000031570	SCV000733270	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735572	SCV000863710	pathogenic	Breast and/or ovarian cancer	2015-11-23	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785225	SCV000923793	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Center for Precision Medicine, Meizhou People's Hospital	RCV002250489	SCV002520808	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000031570	SCV004243684	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732568	SCV005360147	pathogenic	BRCA2-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The BRCA2 c.5682C>G variant is predicted to result in premature protein termination (p.Tyr1894*). This variant has been documented to be causative for multiple cancers including breast, ovarian and prostate (see for example - Risch et al. 2001. PubMed ID: 11179017; Edwards et al. 2010. PubMed ID: 20736950; Dudley et al. 2018. PubMed ID: 29360161). In at least one individual this variant was reported in the compound heterozygous state in an individual with Fanconi anemia (Wagner et al. 2004. PubMed ID: 15070707). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted in ClinVar as pathogenic by multiple submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/37989/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.