Submissions for variant NM_000059.4(BRCA2):c.8489G>A (p.Trp2830Ter)

dbSNP: rs80359101

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)	RCV000077442	SCV000301423	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222775	SCV000271335	pathogenic	Hereditary breast ovarian cancer syndrome	2015-03-23	criteria provided, single submitter	clinical testing	The p.Trp2830X variant in BRCA2 has not been previously reported in individuals with cancer or in large population studies. This nonsense variant leads to a pre mature termination codon at position 2830, which is predicted to lead to a trunc ated or absent protein. Heterozygous loss of BRCA2 function is an established di sease mechanism in BRCA2-associated cancers. In summary, the p.Trp2830X variant is pathogenic for BRCA2-associated cancers in an autosomal dominant manner (http ://www.partners.org/personalizedmedicince/LMM) based upon its predicated impact to the protein and absence in controls.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077442	SCV000327909	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000484831	SCV000572118	pathogenic	not provided	2023-08-02	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Palmero et al., 2018; Rebbeck et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; 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; Also known as 8717G>A; This variant is associated with the following publications: (PMID: 29446198, 29907814, 30760827, 20104584, 31853058)
Ambry Genetics	RCV000569959	SCV000661164	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-02	criteria provided, single submitter	clinical testing	The p.W2830* pathogenic mutation (also known as c.8489G>A), located in coding exon 19 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8489. This changes the amino acid from a tryptophan to a stop codon within coding exon 19. This alteration has been reported in at least 2 unrelated hereditary breast and/or ovarian cancer families (Palmero EI et al. Sci Rep, 2018 06;8:9188; 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484831	SCV001133938	pathogenic	not provided	2019-07-12	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Invitae	RCV000222775	SCV001585862	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2830*) 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 premature translational stop signal has been observed in individual(s) with high risk of hereditary breast and ovarian cancer (HBOC) syndrome (PMID: 29446198, 29907814). ClinVar contains an entry for this variant (Variation ID: 52605). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473423	SCV004212819	pathogenic	Familial cancer of breast	2022-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000222775	SCV004222891	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8489G>A (p.Trp2830X) 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 was absent in 251188 control chromosomes. c.8489G>A has been reported in the literature in individuals at increased risk of Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29446198). Seven submitters, including an expert panel (ENIGMA), have cited 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.
Color Diagnostics, LLC DBA Color Health	RCV000569959	SCV004362755	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	clinical testing	This variant causes a nonsense mutation in exon 20 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 suspected hereditary breast and ovarian cancer families (PMID: 29446198, 29907814). A different mutation resulting in the same nonsense codon has been reported in an individual affected with breast and/or ovarian cancer (PMID: 27165220). 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.
Sharing Clinical Reports Project (SCRP)	RCV000077442	SCV000109240	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-10-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077442	SCV000147383	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing