Submissions for variant NM_000059.4(BRCA2):c.5576_5579del (p.Ile1859fs)

dbSNP: rs80359520

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)	RCV000031556	SCV000282408	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	RCV000044684	SCV000072697	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.Ile1859Lysfs*3) 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 (rs770318608, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8705994, 22160602, 22217648, 23633455, 23683081). This variant is also known as 5803delATTA, 5804del4, and 5574_5577delAATT. ClinVar contains an entry for this variant (Variation ID: 37975). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131118	SCV000186048	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-17	criteria provided, single submitter	clinical testing	The c.5576_5579delTTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5576 to 5579, causing a translational frameshift with a predicted alternate stop codon (p.I1859Kfs*3). This mutation has been reported in numerous hereditary breast and ovarian cancer (HBOC) patients and families world-wide (Foster KA et al. Cancer Res. 1996 Aug;56:3622-5; Gonzalez-Angulo AM et al. Clin. Cancer Res. 2011 Mar;17:1082-9; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Blay P et al. BMC Cancer. 2013 May;13:243; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Kim YC et al. Oncotarget. 2016 Feb;7:9600-12; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Zhao Q et al. J. Gynecol. Oncol. 2017 Jul;28:e39; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Liang Y et al. Med Sci Monit, 2018 Apr;24:2465-2475; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Sunami K et al. Cancer Sci, 2019 Apr;110:1480-1490; Yoshida R et al. Oncotarget, 2019 May;10:3276-3284; Ueda M et al. Obstet Gynecol Int, 2019 May;2019:4365754; El Ansari FZ et al. BMC Cancer, 2020 Aug;20:747; Park CS et al. Asian J Surg, 2020 Oct;43:996-1001; Sirisena N et al. Breast Cancer Res, 2020 05;22:43; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Bang YJ et al. Cancer Res Treat, 2021 Oct). This mutation has also been identified in patients diagnosed with prostate and biliary tract cancer (Wardell CP et al. J Hepatol, 2018 05;68:959-969; Terashima T et al. Oncotarget, 2019 Oct;10:5949-5957; Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376; Power R et al. Fam Cancer, 2021 04;20:97-101). Of note, this alteration is also designated as c.5574_5577delAATT, 5803delATTA and 5804del4 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.
GeneDx	RCV000160296	SCV000210767	pathogenic	not provided	2019-12-18	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 a multiple individuals with a personal or family history consistent with pathogenic variants in this gene (Ikeda 2001, Sugano 2008, Wang 2012, Kang 2015, Kim 2016, Eoh 2017, Pritzlaff 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.5574_5577delAATT or 5804del4; This variant is associated with the following publications: (PMID: 22160602, 23683081, 22798144, 28127413, 28541631, 30203341, 11149425, 8705994, 25863477, 23633455, 19016756, 22713736, 24578176, 26848529, 27914478, 28008555, 27633797, 24094589, 28166811, 29422015, 26681312, 28724667, 29348823, 29020732, 29360550, 21643751, 29752822, 29673794, 30287823, 28111427, 30720243, 30742731, 30702160, 30322717, 31143373, 30309222, 31666926, 32300630, 30291343, 29625052, 26689913, 30350268, 31447099, 29176636, 31214711)
Color Diagnostics, LLC DBA Color Health	RCV000131118	SCV000292136	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-13	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 also known as 5802delTTAA, 5803delATTA, 5804_5808delTTAA, 5804del4 and c.5574_5577delAATT in the literature. This variant is expected to result in unstable variant messenger RNA, which is corroborated by an RNA analysis of allelic imbalance in expressed BRCA2 mRNA transcripts in a heterozygous variant carrier (PMID: 19471317). This variant has been reported in over 30 individuals affected with breast and ovarian cancer (PMID: 8705994, 11149425, 17262179, 20104584, 21233401, 22160602, 22713736, 22798144, 23479189, 23633455, 23683081, 24249303, 24578176, 24728189, 26848529). A Japanese breast cancer case-control study (PMID: 30287823) and a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001464) have reported this variant in 27/7104 cases and 3/23731 unaffected controls and 16/60450 cases and 7/53454 unaffected controls, respectively. This variant also has been reported in a prostate cancer case-control study in 11/7636 prostate cancer cases and 2/12366 unaffected controls (PMID: 31214711). This variant has been identified in 4/244832 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	RCV000160296	SCV000296678	pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing	The BRCA2 c.5576_5579del (p.Ile1859Lysfs*3) 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 the published literature in individuals and families with breast/ovarian cancer (PMIDs: 35918668 (2022), 34645131 (2022), 31143373 (2019), 30287823 (2018), 23683081 (2013), 23633455 (2013), 22713736 (2012), 22217648 (2012), 22160602 (2012), 20104584 (2010)), and biliary track cancer (PMIDs: 32918181 (2021), 31666926 (2019)). The frequency of this variant in the general population, 0.000016 (4/244832 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	RCV000031556	SCV000327232	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000031556	SCV000577957	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000044684	SCV000588101	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160296	SCV000602738	pathogenic	not provided	2023-11-03	criteria provided, single submitter	clinical testing	The BRCA2 c.5576_5579delTTAA; p.Ile1859LysfsTer3 variant (rs80359520), also reported as 5802del4, 5803del4 and 5804del4, has been described in the literature in several individuals and families with breast and ovarian cancer (Foster 1996, George 2013, Schneegans 2012). This variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37975) and is found in the general population with an overall allele frequency of 0.002% (4/244832 alleles) in the Genome Aggregation Database. 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 pathogenic. References: Foster KA et al. Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res. 1996 56(16):3622-5. George J et al. Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin Cancer Res. 2013 19(13):3474-84. Schneegans SM et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012 11(2):181-8.
Department of Medical Genetics, Oslo University Hospital	RCV000031556	SCV000605703	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044684	SCV000605790	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Ile1859LysfsX3 variant in BRCA2 has been reported in >35 individuals with BRCA2-associated cancers (Saghir 2015, Kim 2016, Breast Cancer Information Core database). It has also been identified in 1/15994 African 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 1859 and leads to a premature termination codon 3 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 HBOC. In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282408.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PVS1, PS4, PM2.
Counsyl	RCV000031556	SCV000677685	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044684	SCV000694882	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing	Variant summary: The c.5576_5579delTTAA 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 (c.5585_5588delTGAA, c.5603_5606delACAG, c.5616_5620delAGTAA). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.003% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been cited in numerous affected individuals via the literature and databases, and has been classified by multiple reputable databases and clinical labs as "pathogenic". Taken together, this variant has been classified as as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000160296	SCV000805726	pathogenic	not provided	2017-12-14	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000160296	SCV001449772	pathogenic	not provided	2014-06-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000160296	SCV001716158	pathogenic	not provided	2020-10-12	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Sema4, Sema4	RCV000131118	SCV002536150	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	curation
Laan Lab, Human Genetics Research Group, University of Tartu	RCV000031556	SCV002538627	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000160296	SCV002563164	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000160296	SCV003813750	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160296	SCV004027441	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001289538	SCV004211889	pathogenic	Familial cancer of breast	2023-10-08	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031556	SCV000054161	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031556	SCV000146636	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	RCV000044684	SCV000587774	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353722	SCV000591975	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ile1859Lysfs*3 variant was identified in 72 of 57,640 proband chromosomes (freq: 0.001) from individuals or families with breast or ovarian cancer and in 3 of 47,462 chromosomes (freq: 0.00006) from healthy individuals (Momozawa 2018, Bhaskaran 2019, George 2013, Foster 1996, Haeyoun 2012, Kokichi 2008, Jalkh 2012, Schneegans 2012, Jang 2012, Blay 2013). The variant was identified in dbSNP (rs1255151416) as “NA”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, Color, GeneDx and 17 other submitters), LOVD 3.0 (observed 35x) and UMD-LSDB (observed 26x). The variant was identified in control databases in 4 of 244,832 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15,994 chromosomes (freq: 0.0001), European in 2 of 111,564 chromosomes (freq: 0.00002), and East Asian in 1 of 18,154 chromosomes (freq: 0.00006); it was not observed in the Latino, Ashkenazi Jewish, South Asian, Finnish, or Other populations. The p.Ile1859Lysfs*3 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1859 and leads to a premature stop codon 3 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.
GenomeConnect, ClinGen	RCV000509336	SCV000607032	not provided	Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735566	SCV000863704	pathogenic	Breast and/or ovarian cancer	2009-03-10	no assertion criteria provided	clinical testing
Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Peradeniya	RCV001289538	SCV001477300	pathogenic	Familial cancer of breast	2019-10-19	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000160296	SCV001905806	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000160296	SCV001971735	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000160296	SCV002034197	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV001289538	SCV002520805	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000031556	SCV002588887	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162273	SCV002758332	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research