Submissions for variant NM_000059.4(BRCA2):c.8673_8674del (p.Arg2892fs)

dbSNP: rs80359724

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113985	SCV000301301	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	RCV000045598	SCV000073611	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2892Thrfs*14) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52656). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000222868	SCV000279351	pathogenic	not provided	2015-05-22	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in BRCA2 is denoted c.8673_8674delAA at the cDNA level and p.Arg2892ThrfsX14 (R2892TfsX14) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 8901delAA. The normal sequence, with the bases that are deleted in braces, is TAAC[AA]GACA. The deletion causes a frameshift, which changes an Arginine to a Threonine at codon 2892, and creates a premature stop codon at position 14 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113985	SCV000327945	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000045598	SCV000592219	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222868	SCV000600819	pathogenic	not provided	2015-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509975	SCV000608128	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-24	criteria provided, single submitter	clinical testing	The c.8673_8674delAA pathogenic mutation, located in coding exon 20 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 8673 to 8674, causing a translational frameshift with a predicted alternate stop codon (p.R2892Tfs*14). This mutation was identified in two individuals as part of a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000222868	SCV000883498	pathogenic	not provided	2018-01-18	criteria provided, single submitter	clinical testing	The BRCA2 c.8673_8674delAA; p.Arg2892fs variant (rs80359724), is not reported in the medical literature but is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 52656). This variant is also absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes two nucleotides causing a frameshift, and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000222868	SCV001450098	pathogenic	not provided	2014-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045598	SCV001482236	pathogenic	Hereditary breast ovarian cancer syndrome	2021-02-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8673_8674delAA (p.Arg2892ThrfsX14) 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 was absent in 251318 control chromosomes. c.8673_8674delAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters, including two expert panels (evaluation after 2014) have cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310185	SCV001499780	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000222868	SCV002497660	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460624	SCV004216145	pathogenic	Familial cancer of breast	2023-05-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113985	SCV000147436	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045598	SCV000587967	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000113985	SCV002588926	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing