ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4638del (rs80359462)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031496 SCV000300775 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044457 SCV000072470 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe1546Leufs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 11044354, 14647210, 15131399, 17148771, 21324516, 26296701). This variant is also known as 4862delT and 4866delT in the literature. ClinVar contains an entry for this variant (Variation ID: 37915). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000163113 SCV000213623 pathogenic Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing ​<span style="background-color:initial">The c.4638delT<span style="background-color:initial"> pathogenic mutation, located in coding exon 10 of the BRCA2 <span style="background-color:initial">gene, results from a deletion of one nucleotide at position 4638, causing a translational frameshift with a predicted alternate stop codon (p.F1546Lfs*22)<span style="background-color:initial">. This mutation has been reported in a Polish ovarian and gastric cancer family (Jakubowska A et al. Eur J Hum Genet.<span style="background-color:initial"> 2003 Dec;11(12):955-8). It has also been reported in several other breast and ovarian cancer families (Br. J. Cancer 2000 Nov;83(10):1301-8; Lubinski J et al. Fam. Cance<span style="background-color:initial">r 2004;3(1):1-10; Risch HA et al. J. Natl. Cancer Inst., 2006 Dec;98:1694-706; <span style="background-color:initial">Zhang S et al. Gynecol. Oncol.<span style="background-color:initial"> 2011 May;121(2):353-7; Tung N et al. Cancer, 2015 Jan;121:25-33; <span style="background-color:initial">Ellingson MS et al. Breast Cancer Res. Treat. 2015 Aug<span style="background-color:initial">). This alteration was also 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). Note that this alteration is also referred to as 4866delT and 4862delT 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 RCV000255077 SCV000321461 pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.4638delT at the cDNA level and p.Phe1546LeufsX22 (F1546LfsX22) at the protein level. This deletion is also known as BRCA2 4862delT and 4866delT using alternate nomenclature. The normal sequence, with the base that is deleted in brackets, is CTTTT[delT]GATG. The deletion causes a frameshift, which changes a Phenylalanine to a Leucine at codon 1546, and creates a premature stop codon at position 22 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4638delT has been reported as a disease-causing variant in patients with personal histories of with breast, ovarian, and prostate cancer, respectively (Anglian Breast Cancer Study Group 2000, Zhang 2011, Ellingson 2015, Pritchard 2016). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031496 SCV000327064 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031496 SCV000488820 pathogenic Breast-ovarian cancer, familial 2 2016-06-24 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000044457 SCV000588093 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255077 SCV000600598 pathogenic not provided 2016-09-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163113 SCV000683640 pathogenic Hereditary cancer-predisposing syndrome 2020-12-11 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11044354, 14647210, 21324516, 25186627, 26296701, 27153395), advanced cancer (PMID: 28873162), or pancreatic cancer (PMID: 29506128). This variant has not been identified 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 RCV000044457 SCV000694789 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4638delT (p.Phe1546Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.4647_4650delAGAG/p.Lys1549fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120716 control chromosomes. This variant has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735552 SCV000901111 pathogenic Breast and/or ovarian cancer 2017-09-19 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031496 SCV001429250 uncertain significance Breast-ovarian cancer, familial 2 2019-11-26 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000255077 SCV001449889 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284957 SCV001471058 pathogenic none provided 2019-12-06 criteria provided, single submitter clinical testing The BRCA2 c.4638delT; p.Phe1546fs variant (rs80359462), also known as 4866delT or 4862delT, is reported in individuals with breast, ovarian, prostate, or pancreatic cancer (Jakubowska 2003, Lowery 2018, Pritchard 2016, Tung 2015, Yurgelun 2019). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 37915). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, 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 Jakubowska A et al. A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer. Eur J Hum Genet. 2003 Dec;11(12):955-8. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1;110(10):1067-1074. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Yurgelun MB et al. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med. 2019 Jan;21(1):213-223.
Sharing Clinical Reports Project (SCRP) RCV000031496 SCV000054101 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031496 SCV000146460 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044457 SCV000587720 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735552 SCV000863690 pathogenic Breast and/or ovarian cancer 2015-03-18 no assertion criteria provided clinical testing

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