Submissions for variant NM_000059.4(BRCA2):c.5796_5797del (p.His1932fs)

dbSNP: rs80359537

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)	RCV000113484	SCV000282415	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000257917	SCV000072772	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His1932Glnfs*12) 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 breast, ovarian and/or pancreatic cancer (PMID: 15733268, 16047344, 19619314, 21989927, 23096355, 24145998, 24737347, 25395318). This variant is also known as 6024delTA. ClinVar contains an entry for this variant (Variation ID: 51940). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131106	SCV000186036	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The c.5796_5797delTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5796 to 5797, causing a translational frameshift with a predicted alternate stop codon (p.H1932Qfs*12). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) families to date (Armakolas A et al. Hum Mut. 2002 Jan;19(1):81-2; Pilato B et al. Breast Cancer Res Treat. 2010 Dec;124(3):875-8; Ghiorzo P et al. Fam Cancer. 2012 Mar;11(1):41-7; Coppa A et al. Breast Cancer Res Treat. 2014 Dec;148(3):629-35; Sambiasi D et al. Oncol. Rep., 2014 Jan;31:365-9; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113484	SCV000327284	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000113484	SCV000489220	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000257917	SCV000694903	pathogenic	Hereditary breast ovarian cancer syndrome	2017-03-17	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.5796_5797delTA (p.His1932Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.5799_5802delCCAA/ p.Asn1933fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121048 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in many affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759630	SCV000889079	pathogenic	not provided	2015-10-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131106	SCV000906922	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-11	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 11754111, 17688236, 19619314, 22072316, 23096355, 24145998, 25395318, 26564481), and pancreatic cancer (PMID: 21989927). 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.
GeneDx	RCV000759630	SCV004169203	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing	Frameshift 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 6024_6025del, c.6024delTA, c.6024_6024delTA; This variant is associated with the following publications: (PMID: 18694767, 16162645, 29854283, 24737347, 19619314, 32438681, 20730485, 25395318, 21989927, 10660329, 24010542, 24312913, 23096355, 17688236, 16047344, 15131399, 11754111, 24145998, 15733268, 26295337, 26300996, 29061375, 28943953, 30482293, 29346284, 22072316, 27225819, 17453335, 18298804, 31090900, 32058061, 32885271, 29922827, 31892343, 36292577, 20104584, 36139606, 35409996)
Baylor Genetics	RCV003473366	SCV004212887	pathogenic	Familial cancer of breast	2024-02-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492359	SCV004240332	pathogenic	Breast and/or ovarian cancer	2023-02-24	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113484	SCV000146701	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	RCV000257917	SCV000587800	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358493	SCV001554242	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.His1932Glnfs*12 variant was identified in 8 of 10676 proband chromosomes (frequency: 0.0007) from Italian, American, British, Latin American, Caribbean and Greek individuals or families with breast, ovarian, or pancreatic cancer (Sambiasi 2012, Ramus 2007, Ghiorzo 2012, Dutil 2015, Armakolas 2001). In one of these studies the variant was found to co-occur with a pathogenic BRCA1 variant (c.5266dupC) in one woman with breast cancer (Sambiasi 2012). The variant was also identified in dbSNP (ID: rs1263168799) as “NA”, ClinVar (classified pathogenic, reviewed by an expert panel in 2016; submitters: ENIGMA, Invitae, Ambry Genetics, CIMBA, BIC and 6 other laboratories), LOVD 3.0, and UMD-LSDB (13x as 5-causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.5796_5797del variant is predicted to cause a frameshift which alters the protein's amino acid sequence beginning at codon 1932 and leads to a premature stop codon 13 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000759630	SCV002034924	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000759630	SCV002036425	pathogenic	not provided		no assertion criteria provided	clinical testing