Submissions for variant NM_000059.4(BRCA2):c.6078_6079del (p.Glu2028fs)

dbSNP: rs80359557

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113527	SCV000282419	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113527	SCV000327346	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507291	SCV000600677	pathogenic	not provided	2016-10-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509821	SCV000607778	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-29	criteria provided, single submitter	clinical testing	The c.6078_6079delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6078 to 6079, causing a translational frameshift with a predicted alternate stop codon (p.E2028Rfs*20). This pathogenic mutation, located in the ovarian cancer cluster region of the BRCA2 gene, has been reported in multiple families with breast and/or ovarian cancer (Lubinski J et al.Fam. Cancer 2004; 3(1):1-10). This variant is also designated as 6306delAA. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496245	SCV000694934	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-18	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6078_6079delAA (p.Glu2028Argfs) variant, alternatively also known as 6306delAA and/or 6306_6307delAA, results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay (NMD), which is commonly known mechanisms for disease. If NMD is escaped this variant is expected to truncate multiple functional regions and domains) (one BRCA2 repeat, helical domain, oligonucleotide/oligosaccharide-binding 1 region, OB-folds, and Tower domain; via InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. c.6270_6271delTA, c.6275_6276delTT, c.6333_6337delGAGAA, etc.). This variant is absent in 120736 control chromosomes from ExAC. In a publication, this variant has been reported in three HBOC families without phenotypic and genotypic details in family members (Lubinski_2004). In ClinVar, this variant has been reported in four patients with breast and/or ovarian cancer by clinical laboratories (BIC and Invitae). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496245	SCV001582061	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-31	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: 52003). This variant is also known as 6306delAA. This premature translational stop signal has been observed in individual(s) with a personal and/or family history of BRCA2-related cancers (PMID: 15131399). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu2028Argfs*20) 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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000507291	SCV004027449	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113527	SCV004101325	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-13	criteria provided, single submitter	clinical testing	The BRCA2 c.6078_6079del (p.Glu2028ArgfsTer20) variant, also referred to as c.6306delAA, causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. The p.Glu2028ArgfsTer20 variant has been identified in three families with a history of cancer; however, phenotype details were unavailable (PMID: 15131399). Additionally, this variant was identified in two individuals with a history of breast cancer (PMID: 34284872). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by a ClinVar expert panel. Based on the available evidence, the c.6078_6079del (p.Glu2028ArgfsTer20) variant is classified as pathogenic for hereditary breast and ovarian cancer.
Baylor Genetics	RCV003460598	SCV004216126	pathogenic	Familial cancer of breast	2023-05-19	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113527	SCV000146762	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	RCV000496245	SCV000587821	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research