Submissions for variant NM_000059.4(BRCA2):c.4965C>G (p.Tyr1655Ter)

gnomAD frequency: 0.00004  dbSNP: rs80358721

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031517	SCV000300809	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.
Invitae	RCV000195354	SCV000072546	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1655*) 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 (rs80358721, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast, ovarian and prostate cancer (PMID: 17688236, 20858050, 21709188, 23569316, 24728189, 26681312). This variant is also known as 5685C>G and 5193C>G. ClinVar contains an entry for this variant (Variation ID: 37936). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000128925	SCV000172795	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The p.Y1655* pathogenic mutation (also known as c.4965C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 4965. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation has been identified in breast, ovarian, and prostate cancer patients (Ramus SJ et al. Hum. Mutat. 2007 Dec;28:1207-15; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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	RCV000044533	SCV000210343	pathogenic	not provided	2022-03-29	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; Reported in individuals with histories consistent with pathogenic variants in this gene (Ramus 2007, Sakai 2009, Castro 2013, Song 2014); 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 5193C>G; This variant is associated with the following publications: (PMID: 17688236, 21205087, 19654294, 27376475, 31447099, 25525159, 23569316, 20858050, 23415752, 21913181, 25256924, 22009639, 24728189, 24830819, 25737278, 26295337, 26681312, 24916970, 25085752, 28651617, 28616458, 25186627, 29446198, 28973083, 30720243, 32853339, 32427313, 30787465, 33087929, 32338768, 32719484, 29371908)
Pathway Genomics	RCV000031517	SCV000223757	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031517	SCV000267775	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000195354	SCV000267859	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195354	SCV000271328	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Tyr1655X variant in BRCA2 has been reported in at least 8 individuals with BRCA2-associated cancers (Ramus 2007, Bayraktar 2012, Castro 2013, Chong 2014, Tung 2015, Susswein 2016). This variant has also been identified in 2/125700 European chromosomes by the Genome Aggregation Database (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 nonsense variant leads to a premature termination codon at position 1655, which is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein and low frequency in controls. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2_Supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044533	SCV000296707	pathogenic	not provided	2019-11-18	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported as pathogenic in individuals affected with breast, ovarian, and prostate cancer in the published literature (PMID: 17688236 (2007), 21913181 (2012), 22009639 (2012), 23569316 (2013), 24728189 (2014), 26681312 (2015)). 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	RCV000031517	SCV000327115	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031517	SCV000487907	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128925	SCV000537670	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-24	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 7 individuals affected with breast and/or ovarian cancer and an individual affected with pancreatic cancer (PMID: 21709188, 2200631, 24728189, 25136594, 25186627, 26681312, 28616458, 28726808, 29371908). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 8/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_003110). This variant has been identified in 27 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 2/271452 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.
Department of Pathology and Molecular Medicine, Queen's University	RCV000496311	SCV000588096	pathogenic	not specified	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000044533	SCV000602864	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	The BRCA2 c.4965C>G; p.Tyr1655Ter variant (rs80358721), also known as c.5685C>G or 5193C>G, is reported in the literature in multiple individuals affected with breast and ovarian cancer (Pruss 2014, Ramus 2007, Rebbeck 2018, Susswein 2016, Tung 2015). This variant is reported in ClinVar (Variation ID: 37936), and is only observed on three 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 to be pathogenic. References: Pruss D et al. Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat. 2014 Aug;147(1):119-32. Ramus SJ et al. Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutat. 2007 Dec;28(12):1207-15. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195354	SCV000694816	pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-18	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4965C>G (p.Tyr1655X) 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. p.Arg3128X, p.Glu3111X). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121918 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). It was observed in several breast and/or ovarian cancer patients indicating pathogenicity. It has also been reported 21 times in BIC which supports the fact that this variant is a recurrent mutation. Additionally, a functional study demonstrated the variant to impair homology directed repair activity of BRCA2 which is a known to be important for BRCA2s role in tumor suppression. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762918	SCV000893330	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	2022-02-04	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV001269282	SCV001448626	pathogenic	Fanconi anemia complementation group D1	2020-11-11	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000031517	SCV002526069	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-05-16	criteria provided, single submitter	clinical testing	The BRCA2 c.4965C>G (p.Tyr1655Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant has a maximum subpopulation frequency of 0.0016% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). This variant has been reported in individuals with a personal and/or family history of breast cancer, ovarian cancer, and prostate cancer (PS4; PMID: 17688236, 22009639, 25186627, 26681312, 29446198, 32338768, 32427313, 32853339). A different variant resulting in premature truncation at residue 1655 have also been reported in individuals with breast and/or ovarian cancer (PS1; PMID: 21120943, 25136594, 29446198). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS1, PS4, PM2_supporting.
Revvity Omics, Revvity	RCV000044533	SCV003814415	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473182	SCV004211918	pathogenic	Familial cancer of breast	2023-09-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031517	SCV000054122	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-01-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031517	SCV000146514	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000194794	SCV000223921	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1	2015-02-02	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000195354	SCV000587734	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353669	SCV000591934	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	See BB4874 report for details of MDS lab. Formal assessment needed. This variant is of the type that is expected to cause the disorder and consistent with the disease presentation.
True Health Diagnostics	RCV000128925	SCV000805244	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-30	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785221	SCV000923789	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research