Submissions for variant NM_000059.4(BRCA2):c.755_758del (p.Asp252fs)

dbSNP: rs80359659

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031685	SCV000282444	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	RCV000167860	SCV000073258	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp252Valfs*24) 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 present in population databases (rs80359659, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8589730, 17636422, 18489799, 20104584, 23569316, 24549055). This variant is also known as 982del4 and 983_986del4. ClinVar contains an entry for this variant (Variation ID: 38103). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031685	SCV000195952	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000045245	SCV000210706	pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing	Observed in several individuals with BRCA2-related cancer (Tavtigian et al., 1996, Evans et al., 2008, Borg et al., 2010, Kang et al., 2015, Cao et al., 2016, Yang et al., 2017; Hu et al., 2018; Lerner-Ellis et al., 2021; Frugtniet et al., 2022); 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; 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; Also known as 982_986del; This variant is associated with the following publications: (PMID: 25863477, 19620486, 21913181, 29566657, 30274973, 28888541, 20104584, 8589730, 17636422, 18489799, 23569316, 26852015, 24549055, 27485037, 20167696, 28205045, 28111427, 28152038, 28664506, 22762150, 21570850, 26295337, 9667259, 15131399, 25673166, 16832351, 26556299, 28724667, 30720243, 30014164, 31174498, 30309722, 31090900, 31263054, 31447099, 34399810, 32341426, 31825140, 32918181, 30787465, 31742824, 33087929, 32853339, 31892343, 33037428, 34356066, 34657373, 32885271, 29922827, 29176636)
Ambry Genetics	RCV000162899	SCV000213386	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	clinical testing	The c.755_758delACAG pathogenic mutation, located in coding exon 8 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 755 to 758, causing a translational frameshift with a predicted alternate stop codon (p.D252Vfs*24). This mutation has been described in multiple families with hereditary female and male breast cancer as well as prostate cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7; Machackova E et al. BMC Cancer. 2008 May;8:140; Evans DG et al. Fam. Cancer. 2008 Jul;7:113-7; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57; Cao WM et al. BMC Cancer. 2015 Feb;16:64; Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150). Of note, this alteration is also designated as c.755_758del, c.755_758del4, 983del4, 983delACAG, and c.983_986del4 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768585	SCV000219290	pathogenic	Breast and/or ovarian cancer	2023-04-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162899	SCV000292156	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.754_757delGACA, 982del4 and 983del4 in the literature. RNA analysis on carrier-derived lymphoblastoid cell lines indicates that the variant transcript is degraded by nonsense-mediated decay (PMID: 16170354). This variant has been reported in over 20 individuals and families affected with breast and ovarian cancer worldwide (PMID: 8589730, 9042907, 10359546, 12698193, 17636422, 18489799, 20104584, 22762150, 23569316, 26852015, 28205045, 29566657, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_002182) and individuals affected with prostate cancer (PMID: 23569316, 26556299) and childhood-onset leukemia (PMID: 16931905). Haplotype analysis on carrier families of European ancestry suggests a common origin (PMID: 9585613). This variant has been identified in 3/250934 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000045245	SCV000296717	pathogenic	not provided	2023-05-12	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000012 (3/250934 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in several affected individuals and families with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 21570850 (2011), 24549055 (2014), 25863477 (2015), 26852015 (2016), 28205045 (2017), 29566657 (2018), 35918668 (2022)) as well as in men affected with prostate cancer (PMIDs: 23569316 (2013), 32853339 (2021)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031685	SCV000327681	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031685	SCV000488483	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-15	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000167860	SCV000588071	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167860	SCV000695064	pathogenic	Hereditary breast ovarian cancer syndrome	2016-07-15	criteria provided, single submitter	clinical testing	Variant summary: The c.755_758delACAG (p.Asp252Valfs) variant in BRCA2 gene is a frame shift predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population dataset of ExAC, but has been reported in multiple affected individuals and segregated with the disease in at several families (Gayther, 1999). In addition, multiple clinical diagnostic centers classify variant as Pathogenic. Taken together, the variant was classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000045245	SCV000885106	pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing	The BRCA2 c.755_758delACAG; p.Asp252ValfsTer24 variant (rs80359659), also known in the literature as 982del4 or 983del4, is reported in several patients with breast, ovarian or prostate cancers (Castro 2013, Machackova 2008, Tavtigian 1996). This variant is also classified as pathogenic by an expert review panel in ClinVar (Variation ID: 38103). It is found in the general population with an overall allele frequency of 0.001% (3/250934 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Castro E et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May 10;31(14):1748-57. PMID: 23569316. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008 May 20;8:140. PMID: 18489799. Tavtigian SV et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333-7. PMID: 8589730.
Sema4, Sema4	RCV000162899	SCV002531872	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-07	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000045245	SCV003812553	pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002250492	SCV004216105	pathogenic	Familial cancer of breast	2024-02-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031685	SCV004846817	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-10	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.754_757delGACA, 982del4 and 983del4 in the literature. RNA analysis on carrier-derived lymphoblastoid cell lines indicates that the variant transcript is degraded by nonsense-mediated decay (PMID: 16170354). This variant has been reported in over 20 individuals and families affected with breast and ovarian cancer worldwide (PMID: 8589730, 9042907, 10359546, 12698193, 17636422, 18489799, 20104584, 22762150, 23569316, 26852015, 28205045, 29566657, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_002182) and individuals affected with prostate cancer (PMID: 23569316, 26556299) and childhood-onset leukemia (PMID: 16931905). Haplotype analysis on carrier families of European ancestry suggests a common origin (PMID: 9585613). This variant has been identified in 3/250934 chromosomes 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167860	SCV004848266	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Asp252ValfsX24 variant in BRCA2 has been reported in >60 individuals with BRCA2-related cancers and segregated with disease in at least 10 affected members of one family (Tavitigian 1996, Schrader 2016, Park 2017a, Park 2017b, Wang 2018, BIC database). Additionally, it was classified as Pathogenic on Apr. 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar Variation ID: 38103). This variant has also been identified in 0.005% (1/18384) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 252 and leads to a premature termination codon 24 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2_Supporting.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000167860	SCV005045688	pathogenic	Hereditary breast ovarian cancer syndrome	2018-08-13	criteria provided, single submitter	clinical testing	The c.755_758del (p.Asp252Valfs*24) variant in the BRCA2 gene is located on the exon 9 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asp252Valfs*24), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/pancreatic cancer (PMID: 36980738, 33113089, 37024097, 24549055, 18489799, 26687385). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38103) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (3/250934). Therefore, the c.755_758del (p.Asp252Valfs*24) variant of BRCA2 has been classified as pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031685	SCV005045915	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Sharing Clinical Reports Project (SCRP)	RCV000031685	SCV000054292	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-12-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031685	SCV000147675	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	RCV000167860	SCV000587567	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357226	SCV001552627	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp252Valfs*24 variant was identified in 9 of 13606 proband chromosomes (frequency: 0.0007) from individuals or families with breast, ovarian or prostate cancer and was not identified in 6508 control chromosomes from healthy individuals (Tavtigian 1996, Evans 2008, Machackova 2008, Borg 2010, Castro 2013, Castera 2014, Cao 2016, Park 2017). The variant was also identified in the following databases: dbSNP (ID: rs80359659) as “With Pathogenic allele”, ClinVar (classified as pathogenic by ENIGMA, GeneDx, Ambry Genetics, Invitae, SCRP, and nine other submitters), Genesight-COGR, LOVD 3.0 (3x), UMD-LSDB (27x as causal), BIC Database (62x), and ARUP Laboratories (as definitely pathogenic). The variant was not identified in Cosmic, MutDB or the Zhejiang University Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.755_758del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 252 and leads to a premature stop codon 20 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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250492	SCV002520929	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
Laboratory for Genotyping Development, RIKEN	RCV003162281	SCV002758408	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732577	SCV005345790	pathogenic	BRCA2-related disorder	2024-04-08	no assertion criteria provided	clinical testing	The BRCA2 c.755_758delACAG variant is predicted to result in a frameshift and premature protein termination (p.Asp252Valfs*24). This variant has been reported to be causative for hereditary breast cancer (Park et al. 2017. PubMed ID: 28205045; Wang et al. 2018. PubMed ID: 29566657). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. In ClinVar, this variant is interpreted as pathogenic by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38103/). We classify this variant as pathogenic.