Submissions for variant NM_000059.4(BRCA2):c.5959C>T (p.Gln1987Ter)

dbSNP: rs80358828

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)	RCV000113510	SCV000300956	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000434288	SCV000296644	pathogenic	not provided	2015-07-25	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113510	SCV000327315	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000434288	SCV000515786	pathogenic	not provided	2021-06-24	criteria provided, single submitter	clinical testing	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; Observed in individuals with BRCA2-related cancers (Sun 2017, Li 2018, Rebbeck 2018, Wang 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27135926, 10660329, 25525159, 28263838, 27535533, 28724667, 30968603, 31565484, 29446198, 30078507, 32318955, 32058061, 30702160, 31825140, 30309722)
Ambry Genetics	RCV000567880	SCV000665940	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	clinical testing	The p.Q1987* pathogenic mutation (also known as c.5959C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 5959. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration has been identified in individuals diagnosed with breast cancer, male breast cancer and/or ovarian cancer (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Liang Y et al. Med Sci Monit, 2018 Apr;24:2465-2475; Wang X et al. Mol Genet Genomic Med, 2019 06;7:e677; Santonocito C et al. Cancers (Basel), 2020 May;12:; Vietri MT et al. Eur J Med Genet, 2020 Jun;63:103883; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Color Diagnostics, LLC DBA Color Health	RCV000567880	SCV000683744	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-26	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 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 been reported in 3 individuals affected with prostate cancer and 6 individuals affected with breast or ovarian cancer, including 2 male individuals (PMID: 29681614, 30339520, 30968603, 32058061, 32438681, 34072659, 34653963). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496769	SCV000916871	pathogenic	Hereditary breast ovarian cancer syndrome	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5959C>T (p.Gln1987X) 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 120624 control chromosomes. c.5959C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (see e.g. Azzollini 2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496769	SCV001584606	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1987*) 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: 51973). For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000567880	SCV002536190	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	curation
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795972	SCV005418179	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Supporting
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113510	SCV000146739	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	RCV000496769	SCV000587814	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research