Submissions for variant NM_000059.4(BRCA2):c.5782G>T (p.Glu1928Ter)

dbSNP: rs56253082

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031577	SCV000300933	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	RCV000044754	SCV000072767	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 37996). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 15519522). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1928*) 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).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031577	SCV000327280	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581432	SCV000688950	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-15	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 also known as 6010G>T in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 12048272, 18819001, 27153395). This variant has been identified in 1/250586 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.
Ambry Genetics	RCV000581432	SCV001186557	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-23	criteria provided, single submitter	clinical testing	The p.E1928* pathogenic mutation (also known as c.5782G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5782. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This alteration, referred to as 6010G>T, has been reported in a male diagnosed with breast cancer who also reported a family history of breast cancer in three sisters (Palli D et al. Eur. J. Cancer, 2004 Nov;40:2474-9). 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.
Baylor Genetics	RCV003460518	SCV004216122	pathogenic	Familial cancer of breast	2023-05-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031577	SCV004846644	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	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 individuals affected with breast/ovarian cancer (PMID: 12048272, 18819001, 27153395). This variant has been identified in 1/250586 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	RCV000044754	SCV005202616	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5782G>T (p.Glu1928X) 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. The variant allele was found at a frequency of 4e-06 in 250586 control chromosomes. c.5782G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Palli_2004). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 15519522). ClinVar contains an entry for this variant (Variation ID: 37996). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031577	SCV000054183	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031577	SCV000146698	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1999-04-13	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044754	SCV000587799	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356842	SCV001552113	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	BRCA2, EXON11, c.5782G>T, p.Glu1928*, Heterozygous, PathogenicrnThe BRCA2 p.Glu1928* variant was identified in 1 of 1298 proband chromosomes (frequency: 0.0008) from Brazilian individuals or families with HBOC (Palmero 2018). The variant was also identified in dbSNP (ID: rs56253082) as “With Pathogenic, Uncertain significance allele”, ClinVar (classified as pathogenic by an ENIGMA expert panel, Invitae, CIMBA, Color, BIC, and SCRP), LOVD 3.0 (1x), and UMD-LSDB (3x, classified as 5-causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.5782G>T variant leads to a premature stop codon at position 1928, 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. Assessment Date: 2019/07/04. References (PMIDs): 29907814.