Submissions for variant NM_000059.4(BRCA2):c.5350_5351del (p.Asn1784fs)

dbSNP: rs80359507

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031540	SCV000282406	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	RCV000044639	SCV000072652	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1784Hisfs*2) 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 (rs769126974, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10923033, 21324516, 22006311, 22144684, 23633455). This variant is also known as 5573delAA and 5578delAA. ClinVar contains an entry for this variant (Variation ID: 37959). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074537	SCV000108622	pathogenic	not provided	2020-06-24	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; Not observed at a 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 5578delAA; This variant is associated with the following publications: (PMID: 23569316, 22006311, 23633455, 24504028, 17148771, 8988179, 9150172, 21233401, 11597388, 21324516, 26681312, 17688236, 16683254, 23725378, 21305653, 28008555, 27836010, 24094589, 29371908, 29084914, 28687971, 30720243, 30322717, 26689913, 31447099, 32853339, 32719484, 32338768, 30787465, 33087929, 31360904)
Ambry Genetics	RCV000131110	SCV000186040	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-15	criteria provided, single submitter	clinical testing	The c.5350_5351delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides between positions 5350 and 5351 causing a translational frameshift with a predicted alternate stop codon (p.N1784Hfs*2). This mutation is located in the ovarian cancer cluster region (OCCR) of BRCA2 and has been detected in patients from multiple ovarian cancer series to date (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84). This mutation has also been detected in a prostate cancer patient (Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57) and a male breast cancer patient (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586). Of note, this alteration is also designated as 5573delAA and 5578delAA 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031540	SCV000195990	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074537	SCV000296699	pathogenic	not provided	2023-07-19	criteria provided, single submitter	clinical testing	The BRCA2 c.5350_5351del (p.Asn1784Hisfs*2) variant (also known as 5578delAA and 5573delAA) alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 21324516 (2011), 22006311 (2011), 23633455 (2013), 24504028 (2014)), breast cancer (PMID: 28008555 (2017), 31360904 (2019)), prostate cancer (PMID: 28687971 (2018), 32338768 (2020)), and pancreatic cancer (PMID: 29922827 (2018)). The frequency of this variant in the general population, 0.000032 (1/31198 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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	RCV000031540	SCV000327201	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044639	SCV000605783	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Asn1784HisfsX2 variant in BRCA2 has been identified in >30 individuals with BRCA2-associated cancers (Gayther 1997, Walsh 2011, Zhang 2011, George 2013, Cunningham 2014, Breast Cancer Information Core (BIC) database, Sharing Clinical Reports Project). This variant has been identified in 1/15316 of European chromosomes by the Genome Aggregation Database (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 1784 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4, PM2.
Counsyl	RCV000031540	SCV000677682	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131110	SCV000683699	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-20	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 also known as 5573delAA, 5578delAA, and c.5351_5352delAA in the literature. 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 at least eight individuals affected with ovarian cancer (PMID: 21324516, 22006311, 23633455, 24728189, 29084914), peritoneal cancer (PMID: 22006311) and individuals affected triple-negative or male breast cancer (PMID: 21233401, 28008555) and at least two families affected with both breast and ovarian cancer (PMID: 8988179, 9150172). This variant also has been observed in individuals affected with pancreatic and prostate cancer (PMID: 23569316, 28687971). This variant has been identified in 1/31198 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	RCV000044639	SCV000694862	pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The c.5350_5351delAA variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.5386_5387delGA/p.Asp1796fs). One in-silico tool predicts damaging outcome for this variant. This variant is absent in 122212 control chromosomes. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031540	SCV000744468	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031540	SCV000839933	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-25	criteria provided, single submitter	clinical testing	This c.5350_5351delAA (p.Asn1784Hisfs*2) frameshift variant in the BRCA2 gene is predicted to introduce a premature translation termination codon and has been reported in multiple unrelated individuals with breast, ovarian, prostate, fallopian, and/or peritoneal cancer (PMID: 8988179, 21324516, 22006311, 23569316, 23633455, 24504028). The c.5350_5351delAA (p.Asn1784Hisfs*2) variant in the BRCA2 gene is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000074537	SCV000883477	pathogenic	not provided	2020-08-27	criteria provided, single submitter	clinical testing	The BRCA2 c.5350_5351delAA; p.Asn1784fs variant (rs80359507) has been identified in multiple individuals diagnosed with ovarian, fallopian tube or peritoneal cancer (Gayther 1997, Walsh 2011, Zhang 2011, Cunningham 2014). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37959) and observed in only 1/30754 alleles in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014. 4:4026. Gayther S et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997. 15(1):103-5. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.Proc Natl Acad Sci U S A. 2011. 108(44):18032-7. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.Gynecol Oncol. 2011. 121(2):353-7.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031540	SCV000993555	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-09-07	criteria provided, single submitter	research
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000031540	SCV001251945	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-05-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000074537	SCV001447454	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000074537	SCV002024787	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798045	SCV002043168	pathogenic	Breast and/or ovarian cancer	2022-01-28	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV002243676	SCV002515298	pathogenic	Fanconi anemia complementation group D1	2022-02-01	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000044639	SCV002522182	pathogenic	Hereditary breast ovarian cancer syndrome	2021-08-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131110	SCV002536129	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000031540	SCV002581390	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-02-23	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000031540	SCV003843087	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-08	criteria provided, single submitter	clinical testing	The BRCA2 c.5350_5351del (p.Asn1784HisfsTer2) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has been reported in several individuals with hereditary breast and ovarian cancer (HBOC)-related cancers, including ovarian cancer (PMID: 30322717, 23633455, 21324516, 22006311), breast cancer (PMID: 31360904), pancreatic cancer (PMID: 29922827), and prostate cancer (PMID: 32338768). It has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is also known as 5573delAA and c.5578delAA in the literature. In summary, this variant meets criteria to be classified as pathogenic.
Baylor Genetics	RCV000031540	SCV004041535	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473185	SCV004211933	pathogenic	Familial cancer of breast	2024-03-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001535625	SCV004718772	pathogenic	BRCA2-related disorder	2024-02-01	criteria provided, single submitter	clinical testing	The BRCA2 c.5350_5351delAA variant is predicted to result in a frameshift and premature protein termination (p.Asn1784Hisfs*2). This variant (also described as 5573del and 5578del) has been reported as pathogenic in patients with breast and ovarian cancer (Gayther et al. 1997. PubMed ID: 8988179; Walsh et al. 2011. PubMed ID: 22006311; Cunningham et al. 2014. PubMed ID: 24504028). This variant is reported in 0.0065% of alleles in individuals of non-Finnish European descent in gnomAD (https://gnomad.broadinstitute.org/variant/13-32913836-CAA-C) and it has been reported as pathogenic in ClinVar by multiple clinical labs as well as the ENIGMA expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/37959/). Based on the available evidence, we consider the BRCA2 c.5350_5351del variant to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV000031540	SCV004846562	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-05	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 also known as 5573delAA, 5578delAA, and c.5351_5352delAA in the literature. 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 at least eight individuals affected with ovarian cancer (PMID: 21324516, 22006311, 23633455, 24728189, 29084914), peritoneal cancer (PMID: 22006311) and individuals affected triple-negative or male breast cancer (PMID: 21233401, 28008555) and at least two families affected with both breast and ovarian cancer (PMID: 8988179, 9150172). This variant also has been observed in individuals affected with pancreatic and prostate cancer (PMID: 23569316, 28687971). This variant has been identified in 1/31198 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.
Sharing Clinical Reports Project (SCRP)	RCV000031540	SCV000054145	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031540	SCV000146602	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	RCV000044639	SCV000587763	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353434	SCV000591962	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn1784Hisfsx2 variant was identified in 6 of 9066 proband chromosomes (frequency: 0.0007) from individuals or families with breast, ovarian or prostate cancer (Gayther 1997 PMID:8988179, George 2013 PMID:23633455, Gonzalez-Angulo 2011 PMID:21233401, Walsh 2011 PMID:22006311, Zhang 2011 PMID:21324516, Castro 2013 PMID:23569316). The variant was also identified in the following databases: dbSNP (ID: rs80359507) as “With Pathogenic allele”, ClinVar (reported 14x as pathogenic by ENIGMA, Quest Diagnostics, CIMBA, Invitae, GeneDx, Ambry, University of Michigan, Counsyl, Color Genomics, SCRO, BIC, COGAR), Clinvitae (reported 5x as pathogenic by Invitae , ClinVar and kConFab), LOVD 3.0 (reported 10x as "affects function"), UMD-LSDB (23 records, as 5-causal), BIC Database (reported 33x, as class 5 ), ARUP Laboratories (as definitely pathogenic). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 1 individual with breast cancer. 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.5350_5351delAA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1784 and leads to a premature stop codon 2 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 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	RCV000031540	SCV000733267	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000074537	SCV000778684	pathogenic	not provided	2017-12-12	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535625	SCV001749651	not provided	BRCA2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-18-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000074537	SCV002037534	pathogenic	not provided		no assertion criteria provided	clinical testing