ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6263C>T (p.Thr2088Ile) (rs767567428)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568895 SCV000664784 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415863 SCV000493613 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
Color RCV000568895 SCV000683763 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000487865 SCV000575729 uncertain significance Breast-ovarian cancer, familial 2 2015-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000415863 SCV000616658 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6263C>T at the cDNA level, p.Thr2088Ile (T2088I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant, also defined as BRCA2 6491C>T using alternate nomenclature, has been observed in at least two individuals with ovarian cancer, one whose tumor also demonstrated loss of heterozygosity (Kanchi 2014, Lu 2015). BRCA2 Thr2088Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Thr2088Ile is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Thr2088Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000415863 SCV000694950 uncertain significance not provided 2016-08-29 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6263C>T (p.Thr2088Ile) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome for this substitution . This variant was found in 1/121198 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was reported in at least one ovarian cancer patient however without strong evidence for pathogenicity. In vivo/vitro studies assessing the impact the variant may have on the function of the protein were not published at the time of classification. A reputable database cites the variant as "UV." Therefore, until additional information becomes available, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000464688 SCV000549507 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-02-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2088 of the BRCA2 protein (p.Thr2088Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs767567428, ExAC 0.002%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 24448499, 26689913). ClinVar contains an entry for this variant (Variation ID: 374724). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455182 SCV000538497 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.