ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8167G>C (p.Asp2723His) (rs41293511)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508035 SCV000602850 pathogenic not specified 2016-12-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131674 SCV000186710 pathogenic Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA2) RCV000077429 SCV000147287 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131674 SCV000537677 pathogenic Hereditary cancer-predisposing syndrome 2016-05-17 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077429 SCV000327825 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077429 SCV000489715 pathogenic Breast-ovarian cancer, familial 2 2016-11-11 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077429 SCV000744535 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045436 SCV000592176 pathogenic Hereditary breast and ovarian cancer syndrome 2012-03-13 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077429 SCV000733314 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077429 SCV000244481 pathogenic Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Fulgent Genetics,Fulgent Genetics RCV000763328 SCV000894005 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000074555 SCV000108640 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.8167G>C at the cDNA level, p.Asp2723His (D2723H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant, also reported as BRCA2 8395G>C using alternate nomenclature, has been identified in association with breast, ovarian, and prostate cancer and was reported to completely segregate with breast and ovarian cancer diagnoses in at least 10 families (Pages 2001, Goldgar 2004, Mitra 2008, Solano 2012, Song 2014, Shimelis 2017). BRCA2 Asp2723His was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). Although in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function, functional studies have demonstrated aberrant cellular localization, inability to rescue cell growth, and defective homology-directed repair activity (Wu 2005, Farrugia 2008, Kuznetsov 2008, Jeyasekharan 2013, Guidugli 2018). In addition, BRCA2 Asp2723His was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Based on currently available evidence, we consider this variant to be pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077429 SCV000743344 pathogenic Breast-ovarian cancer, familial 2 2014-10-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045436 SCV000695133 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8167G>C (p.Asp2723His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was absent in 121762 control chromosomes. This variant is a recurrent pathogenic mutation reported in literature and clinical databases with consistent patient and functional data, including support from multifactorial probability model and reported co-segregation with disease. In addition, several clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Therefore, this variant is classified as Pathogenic.
Invitae RCV000045436 SCV000073449 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 2723 of the BRCA2 protein (p.Asp2723His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with breast and ovarian cancer in several families (PMID: 15290653, 16489001). It has also been reported in several unrelated individuals affected with breast and ovarian cancer (PMID: 11207042, 23961350, 24728189). ClinVar contains an entry for this variant (Variation ID: 52515). Experimental studies have shown that this missense change causes the mislocalization of BRCA2 to the cytoplasm (PMID: 15695382, 18607349, 24013206) and disruption of BRCA2 function (PMID: 15695382, 18607349, 23108138, 25146914). A different missense substitution at this codon (c.8168A>G, p.Asp2723Gly) is reported to be deleterious (PMID: 21990134). This indicates that the Asp2723 residue is important for BRCA2 protein function. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074555 SCV000296682 pathogenic not provided 2015-04-20 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045436 SCV000587936 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077429 SCV000109227 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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