ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5857G>T (p.Glu1953Ter) (rs80358814)

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Total submissions: 23
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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) RCV000077363 SCV000300944 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 RCV000195356 SCV000072788 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1953 (p.Glu1953*) of the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80358814, ExAC 0.002%). This variant has been observed in individuals and families affected with breast, ovarian, and prostate cancer (PMID: 9150172, 9792861, 16683254, 23318356, 28008555). It is recognized as a common cause of breast and ovarian cancer in the French Canadian population (PMID: 15382066, 23621881). This variant is also known as 6085G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 51952). 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 RCV000131117 SCV000186047 pathogenic Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000044775 SCV000210373 pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.5857G>T at the cDNA level and p.Glu1953Ter (E1953X) at the protein level. This variant is also known as BRCA2 6085G>T using alternate nomenclature. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported as a French Canadian founder pathogenic variant in multiple hereditary or early-onset breast and/or ovarian cancer families as well as in association with familial prostate cancer (Serova-Sinilnikova 1997, Frank 1998, Tonin 1998, Oros 2004, Zhang 2011, Taherian 2013, Belanger 2015) and is considered pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000195356 SCV000219366 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-08 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000077363 SCV000267789 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000195356 SCV000271331 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Glu1953X variant in BRCA2 has been reported in >35 individuals with BRCA2- associated cancers (Serova-Sinilnikova 1997, Ghadirian 2009, Janavicius 2010, Ta herian 2013, Breast Cancer Information Core (BIC) database). This variant has be en identified in 1/66642 European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs80358814). This frequency is lo w enough to be consistent with the frequency of hereditary breast and ovarian ca ncer (HBOC) in the general population. This nonsense variant leads to a prematur e termination codon at position 1953, which is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism for HBOC. In summary, this variant meets our criteria to be classifie d as pathogenic for HBOC in an autosomal dominant manner based upon the predicte d impact to the protein.
Color RCV000131117 SCV000292172 pathogenic Hereditary cancer-predisposing syndrome 2015-07-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077363 SCV000296600 pathogenic Breast-ovarian cancer, familial 2 2015-10-10 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077363 SCV000327300 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000313209 SCV000383727 pathogenic BRCA2-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The BRCA2 c.5857G>T (p.Glu1953Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Glu1953Ter variant has been reported in at least seven studies in individuals with breast, ovarian or prostate cancer in which it is found in a heterozygous state in at least 44 patients. The variant is a common cause of breast and ovarian cancer in the French Canadian population (Serova-Sinilnikova et al. 1997; Tonin et al. 1998; Oros et al. 2004; van der Hout et al. 2006; Cavallone et al. 2010; Taherian et al. 2014; Ghadirian et al. 2014). Control data are unavailable from these studies for this variant, which is reported at a frequency of 0.00001 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Although the p.Glu1953Ter variant has not been reported in any cases of Fanconi anemia, it is generally accepted that pathogenic variants in the BRCA2 gene also confer carrier status for Fanconi anemia. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Glu1953Ter variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Department of Pathology and Molecular Medicine,Queen's University RCV000195356 SCV000588104 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195356 SCV000592006 pathogenic Hereditary breast and ovarian cancer syndrome 2013-11-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515293 SCV000611179 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3; Tracheoesophageal fistula 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195356 SCV000694907 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The c.5857G>T 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.5864C>A, p.Ser1955X; c.5909C>A, p.Ser1970X; c.5946delT, p.Ser1982fsX22). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0008% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been reported in numerous families and affected individuals in the literature, mainly of French Canadian descent, and has been reported as pathogenic by multiple reputable clinical labs and databases. Taken together, this variant has been classified as a Pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077363 SCV000744478 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044775 SCV000889081 pathogenic not provided 2015-10-10 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735575 SCV000902208 pathogenic Breast and/or ovarian cancer 2017-03-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077363 SCV000109160 pathogenic Breast-ovarian cancer, familial 2 2011-03-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077363 SCV000146715 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 RCV000195356 SCV000587805 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077363 SCV000733274 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735575 SCV000863713 pathogenic Breast and/or ovarian cancer 2015-10-28 no assertion criteria provided clinical testing

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