ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7007G>A (p.Arg2336His) (rs28897743)

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Total submissions: 23
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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) RCV000031659 SCV001161652 pathogenic Breast-ovarian cancer, familial 2 2019-06-18 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 = 0.999037
Invitae RCV000045112 SCV000073125 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2336 of the BRCA2 protein (p.Arg2336His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. It also falls at the last nucleotide of exon 13 of the BRCA2 coding sequence. This variant is not present in population databases (rs28897743, ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer, Fanconia anemia, and acute myelogenous leukemia (PMID: 22486713, 25395318, 12065746, 16115142, 26968956, 22430266). This variant is also known as 7235G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38077). Experimental studies have shown that this missense change causes skipping of exon 13 (PMID: 16792514, 20215541, 22505045), and fails to rescue the lethal loss of Brca2 in mouse embryonic stem cells (PMID: 21719596). A different variant affecting this nucleotide has been also reported in an individual affected with breast and/or ovarian cancer and caused the skipping of exon 13 (PMID: 22505045), indicating that this nucleotide is crucial for normal mRNA splicing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131031 SCV000185961 pathogenic Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing Last nucleotide of exon;Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000174440 SCV000210411 pathogenic not provided 2018-01-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.7007G>A at the cDNA level. Located at the last nucleotide of exon 13, this variant disrupts a natural splice donor site, and multiple functional studies have found this variant to result in skipping of exon 13 (Thomassen 2006, Sanz 2010, Biswas 2011). Although the nucleotide substitution results in the change of an Arginine to a Histidine at codon 2336, and is called Arg2336His in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA2 c.7007G>A, also denoted 7235G>A using alternate nomenclature, has been identified in both male and female breast cancer patients as well as in the compound heterozygous state or homozygous state in at least five individuals with Fanconi Anemia (Howlett 2002, Alter 2007, Machackova 2008, Ahmad 2012, Coppa 2014, Degrolard-Courcet 2014, Bu 2016, Ghazwani 2016, Lang 2017). This variant was not observed in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 7007, is conserved across species. Based on currently available evidence, we consider this variant to be pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174440 SCV000225746 pathogenic not provided 2017-06-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000174440 SCV000296656 pathogenic not provided 2016-10-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031659 SCV000327565 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000475925 SCV000541005 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045112 SCV000592088 pathogenic Hereditary breast and ovarian cancer syndrome 2013-01-22 criteria provided, single submitter clinical testing
Counsyl RCV000031659 SCV000677695 pathogenic Breast-ovarian cancer, familial 2 2015-06-30 criteria provided, single submitter clinical testing
Color RCV000131031 SCV000689020 pathogenic Hereditary cancer-predisposing syndrome 2017-07-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045112 SCV000695022 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7007G>A (p.Arg2336His) alters a conserved last nucleotide located within exon 13 comprising the exonic splice region. At the protein level, it results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes splicing through the canonical 5' splicing donor site. Several publications report experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 13 (example, Sanz_2010, Thomassen_2006, Claes_2004). The variant was absent in 247772 control chromosomes. c.7007G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and Fanconi Anemia (example, Sanz_2010, Thomassen_2006, Konstantopoulou_2008, Ahmad_2012, Biswas_2011, Beristain_2010, Brooks_2006, Ghazwani_2016, Gorski_2004, Peixoto_2014, Siraj_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an inability to rescue the lethality of BRCA2-null mouse embryonic stem cells (Biswas_2011). Fourteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=14)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031659 SCV000744505 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000031659 SCV001139167 pathogenic Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001799 SCV001159457 pathogenic not specified 2018-08-01 criteria provided, single submitter clinical testing The BRCA2 c.7007G>A; p.Arg2336His variant (rs28897743) is reported in the literature in individuals affected with breast and/or ovarian cancer and Fanconi anemia (Ahmad 2012, Coppa 2014, Ghazwani 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 38077), and it is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database) indicating it is not a common polymorphism. This variant occurs in the last nucleotide of exon 13, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with this, transcript analyses demonstrate skipping of exon 13 or exons 12 and 13 in patient cells carrying this variant (Biswas 2011, Houdayer 2012, Sanz 2010). Based on the above information, this variant is considered to be pathogenic. References: Ahmad J et al. Detection of BRCA1/2 mutations in breast cancer patients from Thailand and Pakistan. Clin Genet. 2012 Dec;82(6):594-8 Biswas K et al. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood. 2011 Sep 1;118(9):2430-42. Coppa A et al. Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14. Breast Cancer Res Treat. 2014 Dec;148(3):629-35. Ghazwani Y et al. Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients. Cancer Genet. 2016 Apr;209(4):171-6. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197695 SCV001368474 pathogenic Breast carcinoma 2018-11-06 criteria provided, single submitter clinical testing This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BS1,BP4. This variant was detected in heterozygous state.
OMIM RCV000009923 SCV000030144 pathogenic Fanconi anemia, complementation group D1 2002-07-26 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000031659 SCV000054266 pathogenic Breast-ovarian cancer, familial 2 2012-10-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031659 SCV000146991 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045112 SCV000587878 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031659 SCV000733290 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735595 SCV000863733 pathogenic Breast and/or ovarian cancer 2014-02-10 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000009923 SCV001133114 likely pathogenic Fanconi anemia, complementation group D1 2019-09-26 no assertion criteria provided clinical testing

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