Submissions for variant NM_000059.4(BRCA2):c.8575del (p.Gln2859fs)

gnomAD frequency: 0.00001  dbSNP: rs80359718

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)	RCV000031752	SCV000282459	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	RCV000045564	SCV000073577	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2859Lysfs*4) 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 (rs80359718, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast cancer (PMID: 11304778, 20104584, 23704984, 26360800, 27083775, 27433846). This variant is also known as 8803delC. ClinVar contains an entry for this variant (Variation ID: 38169). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130105	SCV000184935	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	clinical testing	The c.8575delC pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8575, causing a translational frameshift with a predicted alternate stop codon (p.Q2859Kfs*4). This mutation has been reported in several individuals diagnosed with hereditary breast and ovarian cancer (HBOC) syndrome (Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Risch HA et al. J Natl Cancer Inst, 2006 Dec;98:1694-706; Giannini G et al. Breast Cancer Res. Treat. 2006 Nov;100:83-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Seifert BA et al. Clin Cancer Res, 2016 Aug;22:4087-4094; Roed Nielsen H et al. Acta Oncol. 2016 Sep;55:38-44; Nguyen-Dumont T et al. BMC Cancer, 2018 02;18:165; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Petridis C et al. Breast Cancer Res, 2019 05;21:58; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53), as well as an individual with lymphoma (Sprissler R et al. Cancers (Basel), 2020 Jun;12). Of note, this alteration is also designated as 8803delC 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	RCV000218043	SCV000278881	pathogenic	not provided	2023-09-27	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 8803delC; This variant is associated with the following publications: (PMID: 11504767, 30720243, 25685387, 20104584, 10359546, 16760289, 11304778, 18703817, 21324516, 26360800, 26833046, 27083775, 27433846, 31723001, 33087929, 30787465, 32570879, 34308366, 28888541, 34399810, 34887416, 33804961, 31060593, 29446198, 33471991)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218043	SCV000296664	pathogenic	not provided	2020-09-17	criteria provided, single submitter	clinical testing	The BRCA2 c.8575del (p.Gln2859Lysfs*4) 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 with a personal and/or family history of breast and/or ovarian cancer (PMID: 11304778 (2001), 20104584 (2010), and 23704984 (2013)), or prostate cancer (PMID: 27433846 (2016)). The frequency of this variant in the general population, 0.00016 (1/6120 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	RCV000031752	SCV000327928	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000045564	SCV000586983	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130105	SCV000683986	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 20 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: 11304778, 16847550, 17148771, 18703817, 20104584, 21324516, 23704984, 25395318, 27083775), and prostate cancer (PMID: 27433846). This variant has been identified in 1/251220 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.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000031752	SCV001478112	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-12-15	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045564	SCV001748680	pathogenic	Hereditary breast ovarian cancer syndrome	2021-06-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8575delC (p.Gln2859LysfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 251220 control chromosomes. c.8575delC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000031752	SCV002499050	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-02-14	criteria provided, single submitter	clinical testing	PVS1, PM2, PS4
Sema4, Sema4	RCV000130105	SCV002531961	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000218043	SCV002551828	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272033	SCV002556390	pathogenic	Familial cancer of breast	2020-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000218043	SCV003812475	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002272033	SCV004210382	pathogenic	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031752	SCV004846045	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-08	criteria provided, single submitter	clinical testing	The c.8575del (p.Gln2859Lysfs*4) variant in the BRCA2 gene is located on the exon 20 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Gln2859Lysfs*4), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 34680878, 36999648, 34399810, 25685387, 31060593, 32098980). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38169) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/251220). Therefore, the c.8575del (p.Gln2859Lysfs*4) variant of BRCA2 has been classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045564	SCV004847921	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Gln2859LysfsX4 variant in BRCA2 has been reported in >20 individuals with BRCA2-related cancers (Martin 2001, Pritchard 2016, Roed Nielsen 2016, BIC database). It was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2859 and leads to a premature termination codon 4 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). Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 38169). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031752	SCV005045921	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000218043	SCV005197325	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031752	SCV000054360	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031752	SCV000147406	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	RCV000045564	SCV000587961	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353471	SCV000592211	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gln2859LysfsX4 deletion variant was identified in 3 of 4874 proband chromosomes from individuals with breast or ovarian cancer (Borg 2010, Loman 2001, Martin 2001). The variant was also identified in dbSNP (ID: rs80359718) “With pathogenic allele”, HGMD, LOVD, and the BIC database (19X as a variant with clinical importance). The p.Gln2859LysfsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2859 and leads to a premature stop codon 4 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.
BRCAlab, Lund University	RCV000031752	SCV002588925	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing