Submissions for variant NM_000059.4(BRCA2):c.5681dup (p.Tyr1894Ter)

dbSNP: rs80359527

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031569	SCV000282411	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	RCV000044718	SCV000072731	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-14	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 (rs80359527, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11241844, 16683254, 23697973). This variant is also known as 5909insA. ClinVar contains an entry for this variant (Variation ID: 37988). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129296	SCV000184057	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-05	criteria provided, single submitter	clinical testing	The c.5681dupA pathogenic mutation (also known as p.Y1894*), located in coding exon 10 of the BRCA2 gene, results from a duplication of A at position 5681. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This pathogenic mutation has been previously reported in Asian, European, and South American breast/ovarian cohorts (van der Hout AH et al. Hum. Mutat. 2006 Jul;27(7):654-66; Li WF et al. Breast Cancer Res. Treat. 2008 Jul;110(1):99-109; Solano AR et al. Springerplus. 2012 Sep;1:20; Castro M et al. Case Rep. Oncol. 2016 Jul;9(2):387-394; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Palmero EI et al. Sci. Rep. 2018 Jun;8(1):9188). Of note, this alteration is also designated as 5909insA 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	RCV000031569	SCV000327262	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031569	SCV000488449	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000482761	SCV000564787	pathogenic	not provided	2024-09-20	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; Not observed at 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 5909dup; This variant is associated with the following publications: (PMID: 26852015, 15131399, 17851763, 17922257, 29310832, 32879886, 35957908, 36367610, 11241844, 18042939, 21324516, 10550133, 27356891, 16683254, 11897832, 23961350, 27721756, 29061375, 29907814, 23697973, 28724667, 28993434, 30720863, 30720243, 30702160, 30322717, 31447099, 34399810, 31825140, 30787465, 32467295, 33151324, 29922827, 35864222, 33461583)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044718	SCV000605821	pathogenic	Hereditary breast ovarian cancer syndrome	2017-06-12	criteria provided, single submitter	clinical testing	The p.Tyr1894X variant in BRCA2 has been reported in at least 8 individuals here ditary breast and or ovarian cancer (HBOC; Edwards 2001, Li 2008, Solano 2012, B reast Cancer Information Core (BIC) database) and one individual with unknown cl inical status with a possible history of familial breast and/or ovarian cancer w ho underwent genetic screening for BRCA1 and BRCA2 (van der Hout 2006). It was a lso identified in 1/17242 of East Asian chromosomes by the Genome Aggregation Da tabase (gnomAD; http://gnomad.broadinstitude.org; dbSNP rs80359527); however, th is frequency is low enough to be consistent with the frequency of HBOC in the ge neral population. This nonsense variant is a result of a duplication of one base pair at position 5681, which creates a premature termination codon at amino aci d position 1894. This alteration is then predicted to lead to a truncated or abs ent protein. Heterozygous loss of function of the BRCA2 gene is an established d isease mechanism in hereditary breast and ovarian cancer. Moreover, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA e xpert panel (SCV000282411.1). In summary, this variant meets criteria to be clas sified as pathogenic for hereditary breast and ovarian cancer in an autosomal do minant manner based upon predicted impact on the protein, presence in multiple a ffected individuals and low frequency in controls.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482761	SCV000887856	pathogenic	not provided	2024-03-21	criteria provided, single submitter	clinical testing	The BRCA2 c.5681dup (p.Tyr1894*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 36537080 (2023), 30720863 (2019), 30322717 (2018), 28993434 (2018), 18042939 (2007)). The frequency of this variant in the general population, 0.000054 (1/18390 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129296	SCV000911073	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This variant inserts 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 affected with breast or ovarian cancer (PMID: 16683254, 17851763, 27153395, 27463008, 28294317, 28724667, 28993434, 29907814). This variant has been identified in 1/250446 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	RCV000044718	SCV000916895	pathogenic	Hereditary breast ovarian cancer syndrome	2020-09-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5681dupA (p.Tyr1894X) 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 4e-06 in 250446 control chromosomes. c.5681dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples Hamann_2002, Tai_2007, Solano_2012, 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. Ten other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000482761	SCV001334480	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262533	SCV001440450	pathogenic	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001262533	SCV004216173	pathogenic	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031569	SCV004846622	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-19	criteria provided, single submitter	clinical testing	This variant inserts an adenine nucleotide into exon 11 creating a premature stop signal. To our knowledge, functional studies have not been reported for this variant. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16683254, 17851763, 27153395, 28947987, 28294317, 28724667, 28993434, 29907814). This variant has been identified in 1/250446 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.
Sharing Clinical Reports Project (SCRP)	RCV000031569	SCV000054174	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-11-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031569	SCV000146665	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	RCV000044718	SCV000587790	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000482761	SCV001906234	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000482761	SCV001975200	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031569	SCV004243683	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing