ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2095C>T (p.Gln699Ter) (rs878853559)

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Total submissions: 9
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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) RCV000256526 SCV000324047 pathogenic Breast-ovarian cancer, familial 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000229702 SCV000283182 pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln699*) 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 families with breast and/or ovarian cancer (PMID: 23683081). ClinVar contains an entry for this variant (Variation ID: 236835). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000256526 SCV000326655 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000482408 SCV000566006 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.2095C>T at the cDNA level and p.Gln699Ter (Q699X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also defined as BRCA2 2323C>T using alternate nomenclature, has been reported in breast and ovarian cancer families (Blay 2013) and is considered pathogenic.
Yang An-Suei Laboratory,Academia Sinica RCV000494713 SCV000583411 pathogenic Neoplasm of the breast criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482408 SCV000600500 pathogenic not provided 2016-09-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000510002 SCV000608277 pathogenic Hereditary cancer-predisposing syndrome 2018-03-22 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)
Color RCV000510002 SCV000905235 pathogenic Hereditary cancer-predisposing syndrome 2017-12-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000229702 SCV000917044 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2095C>T (p.Gln699X) 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. The variant was absent in 245908 control chromosomes (gnomAD). The variant, c.2095C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Blay_2013, Wang_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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