ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8167G>C (p.Asp2723His)

gnomAD frequency: 0.00001  dbSNP: rs41293511
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Total submissions: 25
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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) RCV000077429 SCV000244481 pathogenic Breast-ovarian cancer, familial, susceptibility to, 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
Invitae RCV000045436 SCV000073449 pathogenic Hereditary breast ovarian cancer syndrome 2021-12-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 2723 of the BRCA2 protein (p.Asp2723His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 11207042, 15290653, 16489001, 23961350, 24728189). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52515). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA2 protein function. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 15695382, 18607349, 23108138, 24013206, 25146914). This variant disrupts the p.Asp2723 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21990134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074555 SCV000108640 pathogenic not provided 2022-07-06 criteria provided, single submitter clinical testing Observed in individuals with personal and family history of BRCA-related cancers, segregating with disease in at least 10 families (Pages et al., 2001; Goldgar et al., 2004; Mitra et al., 2008; Solano et al., 2012; Song et al., 2014; Shimelis et al., 2017); Published functional studies demonstrate a damaging effect: aberrant cellular localization, inability to rescue cell growth, and defective homology-directed repair activity (Wu et al., 2005; Farrugia et al., 2008; Kuznetsov et al., 2008; Jeyasekharan et al., 2013; Guidugli et al., 2018; Hart et al., 2019); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor et al., 2012); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8395G>C; This variant is associated with the following publications: (PMID: 24728189, 15695382, 18451181, 18182994, 25447315, 23961350, 25085752, 11207042, 21702907, 22505045, 24323938, 25146914, 25782689, 24013206, 15290653, 19043619, 23108138, 18607349, 16489001, 27225637, 20223037, 26775038, 28283652, 28324225, 26586665, 28008555, 27550963, 26681312, 28158555, 29394989, 29446198, 29988080, 30322717, 30309722, 31263054, 32444794, 30696104, 34399810, 30787465, 35464868, 12228710, 29884841, 33964450, 21990134)
Ambry Genetics RCV000131674 SCV000186710 pathogenic Hereditary cancer-predisposing syndrome 2019-03-26 criteria provided, single submitter clinical testing The p.D2723H pathogenic mutation (also known as c.8167G>C), located in coding exon 17 of the BRCA2 gene, results from a G to C substitution at nucleotide position 8167. The aspartic acid at codon 2723 is replaced by histidine, an amino acid with some similar properties. This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Goldgar DE et al. Am. J. Hum. Genet. 2004 Oct;75:535-44; Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83​; Tavtigian SV et al. Hum. Mutat. 2008 Nov;29:1342-54; Karchin R et al. Cancer Inform. 2008 Apr;6:203-16; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Moreover, functional studies have shown that this alteration affects the DNA repair function of BRCA2 (Wu K et al. Cancer Res. 2005 Jan;65:417-26; Farrugia DJ et al. Cancer Res. 2008 May;68:3523-31​; Kuznetsov SG et al. Nat. Med. 2008 Aug;14:875–881; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102:233-248). Additionally, this alteration has been detected in multiple hereditary breast and ovarian cancer families, including families with male breast cancer (Pages S et al. Br. J. Cancer. 2001 Feb;84:482-8; Goldgar DE et al. Am. J. Hum. Genet. 2004 Oct;75:535-44; Wu K et al. Cancer Res. 2005 Jan;65:417-26; Solano AR et al. Springerplus. 2012 Sep;1:20; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this alteration is also designated as 8395G>C in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074555 SCV000296682 pathogenic not provided 2019-12-06 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant has been reported to segregate with disease.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077429 SCV000327825 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077429 SCV000489715 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-11-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131674 SCV000537677 pathogenic Hereditary cancer-predisposing syndrome 2020-06-08 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with histidine at codon 2723 in the DNA binding domain of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes the mislocalization of BRCA2 to the cytoplasm (PMID: 15695382, 18607349, 24013206) and disrupt BRCA2 function, including homology-directed DNA repair activity (PMID: 15695382, 18607349, 19043619, 23108138, 25146914). This variant has been reported in multiple individuals affected with breast and/or ovarian cancer (PMID: 11207042, 23961350, 24052750, 24728189) and with prostate cancer (PMID: 23569316). Multifactorial analyses based on numerous individuals' personal and family history of cancer and tumor pathology have determined this variant to be disease-causing (PMID: 15290653, 16489001, 18451181, 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same codon, p.Asp2723Gly, is known to be pathogenic (Clinvar variation ID: 38141), indicating that arginine at this position is important for BRCA2 function. Based on the available evidence, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508035 SCV000602850 pathogenic not specified 2016-12-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045436 SCV000695133 pathogenic Hereditary breast 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000077429 SCV000743344 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2014-10-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077429 SCV000744535 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-09-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763328 SCV000894005 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170973 SCV001333633 pathogenic Breast and/or ovarian cancer 2018-01-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000045436 SCV001653096 pathogenic Hereditary breast ovarian cancer syndrome 2020-06-12 criteria provided, single submitter clinical testing The p.Asp2723His variant in BRCA2 has been identified in >20 individuals with BRCA2-associated cancers and segregated with disease with multiple individuals from many families (Pages 2001 PMID: 11207042, Goldgar 2004 PMID: 15290653, Chenevix-Trench 2006 PMID: 16489001, Solano 2012 PMID: 23961350, Song 2014 PMID: 24728189). This variant was absent from large population studies. In vitro and in vivo functional studies support an impact on protein function (Chenevix-Trench 2006 PMID: 16489001, Wu 2005 PMID: 15695382, Farrugia 2008 PMID: 18451181, Kuznetsov 2008 PMID: 18607349, Jeyasekharan 2013 PMID: 24013206, Guidugli 2018 PMID: 29394989) and computational prediction tools and conservation analysis are consistent with pathogenicity. Moreover, this variant as well as another variant involving this codon (p.Asp2723Gly) have been classified as pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (SCV000244481.1). Multiple other variants involving this codon have also been identified in individuals with HBOC (ClinVar, HGMD: Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PS4, PS3_Supporting, PP1_Moderate, PM2, PM5, PP3.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV000045436 SCV002025844 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-16 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077429 SCV000109227 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077429 SCV000147287 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045436 SCV000587936 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353843 SCV000592176 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Asp2723His variant is identified in the literature in 5 out of 554 proband chromosomes (frequency 0.009) in individuals with breast (male and female), ovarian and prostate cancers, however it is not analyzed in enough control chromosomes to determine the population frequency (0 out of 380, frequency=0) (Chenevix-Trench 2006, Mitra 2008, Pages 2001, Ding 2011). Furthermore, It is listed in dbSNP database as coming from a "clinical source" (ID#: rs41293511) with no frequency information available, and therefore, not informative to assess the frequency of this variant in the general population. The p.Asp2723 residue is conserved in mammals and other species and computational analyses (SIFT, Polyphen2, AlignGVGD) predict deleterious impact on the protein function. In addition, in vitro functional studies shows impaired BRCA2 function (Kuzentsov 2008, Wu 2005, Karchin 2008, Walker 2010, Carvalho_2007) and multifactorial likelihood-ratio models shows higher odds in favor of causality for this variant (Goldgar 2004, Farrugia 2008, Chenevix-Trench 2006). In the UMD database, this variant has been identified as an isolated "pathogenous" variant in 19 individuals with breast or ovarian cancers, increasing the likelihood this variant is clinically important. Other variants at the same location include p.Asp2723Gly (5 times in UMD), p.Asp2723Val (2 times in UMD) and p.Asp2723Glu (1 time). The p.Asp2723Gly has been shown to result in loss of the last 164 nucleotides of exon18, and shown to be deleterious by several studies (Farrugia 2008, Easton 2007, Karchin 2008), increasing the likelihood that an alteration to this residue is pathogenic. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077429 SCV000733314 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing
CZECANCA consortium RCV001391219 SCV001593135 pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided case-control
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000074555 SCV001951051 pathogenic not provided no assertion criteria provided clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000045436 SCV001977037 pathogenic Hereditary breast ovarian cancer syndrome 2021-09-27 no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000074555 SCV002019208 pathogenic not provided 2019-08-07 no assertion criteria provided clinical testing

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