ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8167G>C (p.Asp2723His) (rs41293511)

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Total submissions: 21
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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 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 and ovarian cancer syndrome 2020-10-18 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 observed 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.
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.
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 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
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 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.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077429 SCV000743344 pathogenic Breast-ovarian cancer, familial 2 2014-10-08 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
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
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,Partners HealthCare Personalized Medicine RCV000045436 SCV001653096 pathogenic Hereditary breast and 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.
Sharing Clinical Reports Project (SCRP) RCV000077429 SCV000109227 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077429 SCV000147287 uncertain significance Breast-ovarian cancer, familial 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 and 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 2 no assertion criteria provided clinical testing
CZECANCA consortium RCV001391219 SCV001593135 pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided case-control

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