ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8756G>T (p.Gly2919Val) (rs80359131)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130693 SCV000185580 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113996 SCV000147455 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000130693 SCV000911706 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
Counsyl RCV000113996 SCV000785018 uncertain significance Breast-ovarian cancer, familial 2 2017-03-13 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000113996 SCV000744549 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000113996 SCV000733324 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
GeneDx RCV000766295 SCV000569297 uncertain significance not provided 2016-11-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8756G>T at the cDNA level, p.Gly2919Val (G2919V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 8984G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly2919Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Gly2919Val occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gly2919Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000479246 SCV000917014 uncertain significance not specified 2018-08-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8756G>T (p.Gly2919Val) results in a non-conservative amino acid change in the encoded protein sequence located within an exonic-splice region close to the exon (22)-intron (21) boundary of the BRCA2 gene. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 119610 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8756G>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000045621 SCV000073634 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 2919 of the BRCA2 protein (p.Gly2919Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). However, in one of these individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.8756G>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 52673). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be neutral (PMID: 19043619). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479246 SCV000600823 uncertain significance not specified 2017-06-06 criteria provided, single submitter clinical testing

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