Submissions for variant NM_000059.4(BRCA2):c.4478_4481del (p.Glu1493fs)

dbSNP: rs80359454

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077327	SCV000282393	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.
Invitae	RCV000195401	SCV000072434	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1493Valfs*10) 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 (rs776022857, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with female breast and ovarian cancer, male breast cancer, and prostate cancer (PMID: 8589730, 11179017, 15131399, 20927582, 21324516, 21952622, 22798144). This variant is also known as 4706del4. ClinVar contains an entry for this variant (Variation ID: 51653). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131081	SCV000186011	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	clinical testing	The c.4478_4481delAAAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4478 to 4481, causing a translational frameshift with a predicted alternate stop codon (p.E1493Vfs*10). This pathogenic mutation has been reported in multiple families affected with breast, ovarian and/or prostate cancer (Tavtigian SV et al. Nat. Genet., 1996 Mar;12:333-7; Frank TS et al. J Clin Oncol, 1998 Jul;16:2417-25; Risch HA et al. Am J Hum Genet, 2001 Mar;68:700-10; Lubinski J et al. Fam Cancer, 2004;3:1-10; Ding YC et al. Breast Cancer Res Treat, 2011 Apr;126:771-8; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Kote-Jarai Z et al. Br J Cancer, 2011 Oct;105:1230-4; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; McVeigh TP et al. Ir J Med Sci, 2014 Jun;183:199-206; Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Dudley B et al. Cancer, 2018 04;124:1691-1700; Mijuskovic M et al. Br J Cancer, 2018 07;119:96-104; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	RCV000044421	SCV000210810	pathogenic	not provided	2021-01-28	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; Observed in individuals with hereditary breast and ovarian cancer (Tavtigian 1996, Meindl 2002, Zhang 2011, Kim 2012, Dudley 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27488020, 27836010, 26681312, 29360161, 30720243, 28176296, 8589730, 11802209, 21324516, 22798144, 21952622, 26187060, 23569316, 10359546, 17148771, 9667259, 20927582, 16162645, 27225637, 29371908, 29478780, 29915322, 27153395, 11179017, 15131399, 30702160, 30322717, 32885271, 32338768)
Counsyl	RCV000077327	SCV000220668	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-09-04	criteria provided, single submitter	literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077327	SCV000327042	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000195401	SCV000588092	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044421	SCV000600589	pathogenic	not provided	2021-04-20	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in individuals and families affected with breast or ovarian cancer in the published literature (PMID: 27153395 (2016), 23884708 (2014), 22798144 (2012), 21952622 (2011), 21324516 (2011)). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000044421	SCV000602836	pathogenic	not provided	2023-11-07	criteria provided, single submitter	clinical testing	The BRCA2 c.4478_4481del; p.Glu1493ValfsTer10 variant (rs80359454), also known as 4706del for legacy nomenclature, is reported in multiple individuals and families with hereditary breast and ovarian cancer syndrome (Dudley 2018, Kote-Jarai 2011, Le 2022, Tavtigian 1996, Zhang 2011). This variant is also classified as pathogenic by an expert review panel in the ClinVar Database (Variation ID: 51653). It is observed on four 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: Dudley B et al. Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy. Cancer. 2018 Apr 15;124(8):1691-1700. PMID: 29360161. Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011 Oct 11;105(8):1230-4. PMID: 21952622. Le TN et al. BRCA1/2 Mutations in Vietnamese Patients with Hereditary Breast and Ovarian Cancer Syndrome. Genes (Basel). 2022 Jan 29;13(2):268. PMID: 35205313. 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. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. PMID: 21324516.
Color Diagnostics, LLC DBA Color Health	RCV000131081	SCV000683623	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This variant deletes 4 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 over 10 individuals affected with ovarian cancer (PMID: 11972384, 20406929, 21324516, 22711857, 23165508, 23791828, 23884708, 24728189), and individuals affected with breast cancer (PMID: 20950396, 22798144, 33758026, 33471991; Leiden Open Variation Database DB-ID BRCA2_001792, Color internal data). This variant has been identified in 4/250362 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195401	SCV000694775	pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-04	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 variant, c.4478_4481delAAAG (p.Glu1493Valfs), causes a frameshift resulting in a premature stop codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable clinical laboratories/databases cite the variant with a classification of "pathogenic." Therefore, the variant of interest is classified as Pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000722037	SCV000853214	pathogenic	Diffuse intrinsic pontine glioma	2017-06-09	criteria provided, single submitter	clinical testing	This is a frameshift alteration in which four nucleotides are deleted (coding nucleotides 4478 through 4481) and is predicted to change a Glutamic Acid to a Valine at amino acid codon 1493, shift the reading frame and result in a premature stop codon 10 amino acids downstream. Classification criteria: PVS1, PM2, PP1.
Molecular Endocrinology Laboratory, Christian Medical College	RCV000077327	SCV002004008	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000044421	SCV003816134	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147333	SCV003835165	pathogenic	Familial cancer of breast	2021-06-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000044421	SCV003917271	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492352	SCV004240313	pathogenic	Breast and/or ovarian cancer	2023-06-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077327	SCV000109124	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-02-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077327	SCV000146433	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	RCV000195401	SCV000587714	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354234	SCV001548796	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu1493Valfs*10 variant was identified in 12 of 17460 proband chromosomes (frequency: 0.0007) from individuals or families with prostate, breast or ovarian cancer (Beetstra 2006, Ding 2011, Fong 2010, Kim 2012, Kote-Jarai 2011, Lubinski 2004, Peto 1999, Risch 2001, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359454) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and twelve other submitters), LOVD 3.0 (19x as pathogenic ), and UMD-LSDB (1x as 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 variant was shown to have a partial response to platinum-based therapy according to the Response Evaluation Criteria in Solid Tumors and Gynecologic Cancer Intergroup Response criteria (Fong 2010). The c.4478_4481del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1493 and leads to a premature stop codon at position 1502. 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 (HBOC) 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	RCV000044421	SCV001740090	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000044421	SCV001906386	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162375	SCV002758425	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077327	SCV004243632	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing