ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2409T>G (p.Tyr803Ter) (rs80358504)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573627 SCV000661153 pathogenic Hereditary cancer-predisposing syndrome 2016-06-20 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031365 SCV000146038 pathogenic Breast-ovarian cancer, familial 2 1999-12-30 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769686 SCV000901099 pathogenic Breast and/or ovarian cancer 2017-04-19 criteria provided, single submitter clinical testing
Color RCV000573627 SCV000905006 pathogenic Hereditary cancer-predisposing syndrome 2017-03-29 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031365 SCV000326700 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000043984 SCV000591806 pathogenic Hereditary breast and ovarian cancer syndrome 2014-03-24 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031365 SCV000300516 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000212221 SCV000210287 pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.2409T>G at the cDNA level and p.Tyr803Ter (Y803X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as 2637T>G using alternate nomenclature, has been reported in association with ovarian cancer and is considered pathogenic (Zhang 2011, Alsop 2012).
Integrated Genetics/Laboratory Corporation of America RCV000043984 SCV000694604 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-02 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2409T>G (p.Tyr803X) 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 likely pathogenic/pathogenic by our laboratory (e.g. c.2480dupA (p.Asn827fsX3), c.2517C>A (p.Tyr839X), and c.2564_2565delCA (p.Thr855fsX25). The variant of interest has not been observed in controls (ExAC) and multiple publications/database has cited the variant in affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Therefore, the variant of interest has been classified as "pathogenic."
Invitae RCV000043984 SCV000071997 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr803*) 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 reported in the literature in individuals affected with ovarian cancer (PMID: 21324516, 22711857). ClinVar contains an entry for this variant (Variation ID: 37784). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000043984 SCV000605811 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-27 criteria provided, single submitter clinical testing The p.Tyr803X variant in BRCA2 has been reported in at least 2 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database, Zhang 2 011) and was absent from large population studies. This nonsense variant leads t o a premature termination codon at position 803, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC) . In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300516.2). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an au tosomal dominant manner based upon the predicted impact to the protein.
PreventionGenetics RCV000212221 SCV000805673 pathogenic not provided 2018-01-04 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000043984 SCV000587631 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031365 SCV000053970 pathogenic Breast-ovarian cancer, familial 2 2011-09-21 no assertion criteria provided clinical testing

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