Submissions for variant NM_000059.4(BRCA2):c.8364G>A (p.Trp2788Ter)

dbSNP: rs397507981

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241319	SCV000301268	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.
Ambry Genetics	RCV000216791	SCV000274881	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-25	criteria provided, single submitter	clinical testing	The p.W2788* pathogenic mutation (also known as c.8364G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8364. This changes the amino acid from a tryptophan to a stop codon within coding exon 18. This mutation has been detected in multiple individuals with breast and/or ovarian cancer (Thomassen et al. Acta Oncol 2008;47(4):772-7; Lecarpentier J et al. Breast Cancer Res. 2012 Jul;14:R99; Sun et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Labidi-Galy et al. Clin. Cancer Res. 2018 01;24(2):326-333; Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620; Bhaskaran et al. Int. J. Cancer 2019 Aug;145(4):962-973; Fostira et al. J. Med. Genet. 2019 Jul; Wang et al. Mol Genet Genomic Med 2019 Jun;7(6):e677). Of note, this alteration is also designated as 8592G>A 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.
GeneDx	RCV000236926	SCV000293487	pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Konstantopoulou et al., 2014; Sun et al., 2017; Mathias et al., 2019; Wang et al., 2019; De Talhouet et al., 2020); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8592G>A; This variant is associated with the following publications: (PMID: 18489799, 24010542, 28724667, 31432501, 30968603, 32341426, 29084914, 26028024, 31209999, 24156927, 23772696, 26300996, 22762150, 31825140, 30702160, 29446198)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241319	SCV000327879	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236926	SCV000887938	pathogenic	not provided	2018-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216791	SCV000906578	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 19 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 not been identified 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.
CeGaT Center for Human Genetics Tuebingen	RCV000236926	SCV001249497	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV000496647	SCV001588176	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp2788*) 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 has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52566). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000241319	SCV001711931	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-20	criteria provided, single submitter	clinical testing	This BRCA2 nonsense variant has been reported in multiple individuals affected with hereditary breast and ovarian cancer. It results in a premature stop codon in exon 19 likely leading to nonsense-mediated decay and lack of protein production. This variant is absent from a large population database and has an entry in ClinVar. We consider c.8364G>A to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496647	SCV003844377	pathogenic	Hereditary breast ovarian cancer syndrome	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8364G>A (p.Trp2788X) 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 251424 control chromosomes. c.8364G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496647	SCV000587951	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000241319	SCV000733317	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000236926	SCV001905940	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162391	SCV002758142	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research