ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2368G>T (p.Glu790Ter) (rs398122746)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077684 SCV000326693 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077684 SCV000300512 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 RCV000657661 SCV000779410 pathogenic not provided 2017-04-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.2368G>T at the cDNA level and p.Glu790Ter (E790X) at the protein level. 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. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000507480 SCV000694603 pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-21 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2368G>T (p.Glu790X) 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.2389G>T [p.Glu797X], c.2603C>G [p.Ser868X], and c.2675T>A [p.Leu892X]). One in silico tool, Mutation Taster, predicts a damaging outcome for this variant. This variant is absent in the large control population database ExAC (0/120798 control chromosomes). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. However, the variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as "pathogenic."
Invitae RCV000507480 SCV000831665 pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu790*) 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 an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91776). 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 RCV000507480 SCV000605786 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-31 criteria provided, single submitter clinical testing The p.Glu790X variant in BRCA2 has not been previously reported in individuals w ith BRCA2-associated cancers or in large population studies. This nonsense varia nt leads to a premature termination codon at position 790, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRC A2 gene is an established disease mechanism in hereditary breast and ovarian can cer (HBOC). In summary, this variant meets our criteria to be classified as path ogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PM2.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077684 SCV000296729 pathogenic Breast-ovarian cancer, familial 2 2015-02-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657661 SCV000887771 pathogenic not provided 2015-02-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077684 SCV000109487 pathogenic Breast-ovarian cancer, familial 2 2010-11-01 no assertion criteria provided clinical testing

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