Submissions for variant NM_000059.4(BRCA2):c.1376T>G (p.Leu459Ter)

dbSNP: rs587781799

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000257539	SCV000323986	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000257539	SCV000326546	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000496394	SCV001581850	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-27	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 266632). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu459*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496394	SCV000587595	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357455	SCV001552934	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu459* variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs587781799) as “With Pathogenic allele”, ClinVar (as pathogenic by ENIGMA, CIMBA, and COGR, reviewed by an expert panel), and LOVD 3.0 (2x as pathogenic). The variant was not identified in the following databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Leu459* variant leads to a premature stop codon at position 459 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.