ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7758G>A (p.Trp2586Ter) (rs80359004)

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Total submissions: 11
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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) RCV000031698 SCV000301200 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 RCV000255811 SCV000321477 pathogenic not provided 2017-09-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7758G>A at the cDNA level and p.Trp2586Ter (W2586X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as 7986G>A using alternate nomenclature, has been reported several individuals with Hereditary Breast and Ovarian Cancer syndrome (Meindl 2002, Jonsson 2005, Callahan 2007, Conner 2014, Nahleh 2015). This variant is considered pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031698 SCV000327725 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000496860 SCV000605818 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-13 criteria provided, single submitter clinical testing The p.Trp2586X variant in BRCA2 has been reported >5 individuals with BRCA2-asso ciated cancers (Meindl 2002, Callahan 2007, Conner 2014, Nahleh 2015, and Breast Cancer Information Core (BIC) database) and was absent from large population st udies. This nonsense variant leads to a premature termination codon at position 2586, 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 heredi tary 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 SCV000301200.2). In summary, this variant meets criteria to be classifie d as pathogenic for HBOC in an autosomal dominant manner based upon absence in c ontrols and the predicted impact to the protein.
Ambry Genetics RCV000569377 SCV000665943 pathogenic Hereditary cancer-predisposing syndrome 2017-03-27 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)
Integrated Genetics/Laboratory Corporation of America RCV000496860 SCV000695099 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-04 criteria provided, single submitter clinical testing Variant summary: The BRCA2 variant, c.7758G>A (p.Trp2586X) causes a nonsense mutation involving a conserved nucleotide resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255811 SCV000887923 pathogenic not provided 2018-06-06 criteria provided, single submitter clinical testing
Color RCV000569377 SCV000905022 pathogenic Hereditary cancer-predisposing syndrome 2018-05-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031698 SCV000054305 pathogenic Breast-ovarian cancer, familial 2 2008-06-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031698 SCV000147173 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496860 SCV000587906 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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