ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9227G>A (p.Gly3076Glu) (rs80359187)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216816 SCV000274761 pathogenic Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing The p.G3076E pathogenic mutation (also known as c.9227G>A), located in coding exon 23 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9227. The glycine at codon 3076 is replaced by glutamic acid, an amino acid with similar properties.This alteration has been reported in a Japanese breast cancer patient and in a familial pancreatic and breast cancer kindred (Ikeda N et al. Int. J. Cancer. 2001 Jan;91:83-8; Hahn SA et al. J. Natl. Cancer. Inst. 2003 Feb;95:214-21). This alteration has been predicted to be pathogenic using homology-directed DNA break repair (HDR) functional assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80). Additionally, this alteration has been predicted to be likely deleterious using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). Based on our internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Yang H et al. Science. 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000221088 SCV000279359 likely pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9227G>A at the cDNA level, p.Gly3076Glu (G3076E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant, also published as BRCA2 9455G>A using alternate nomenclature, has been reported in at least one individual with breast cancer (Ikeda 2001). Han et al. (2003) also identified BRCA2 Gly3076Glu in three family members, two of whom were diagnosed with both breast and pancreatic cancer and one diagnosed with breast cancer only. Additionally, BRCA2 Gly3076Glu displayed reduced homologous recombination repair activity in a homology-directed DNA break repair assay, which has been shown to have high sensitivity and specificity for determining pathogenicity of BRCA2 missense variants in the DNA-binding domain (Guidugli 2013). Additionally, a multifactorial analysis taking into account these functional results predicts this variant to be pathogenic (Guidugli 2018). BRCA2 Gly3076Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Gly3076Glu is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available information, we consider BRCA2 Gly3076Glu to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000114069 SCV000296594 uncertain significance Breast-ovarian cancer, familial 2 2016-03-19 criteria provided, single submitter clinical testing
Counsyl RCV000114069 SCV000489258 uncertain significance Breast-ovarian cancer, familial 2 2016-09-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286967 SCV001473600 likely pathogenic none provided 2019-10-02 criteria provided, single submitter clinical testing The BRCA2 c.9227G>A; p.Gly3076Glu variant (rs80359187) is reported in the literature in multiple individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (Alemar 2017, Hahn 2003, Ikeda 2001, Li 2018). In one family, this variant segregated with disease in at least three affected family members (Hahn 2003). This variant is found on a single chromosome in the Genome Aggregation Database (1/250980 alleles), indicating it is not a common polymorphism. The glycine at codon 3076 is highly conserved, and functional analyses indicate decreased activity in assays of homology-directed recombination (HDR) (Guidugli 2013, Guidugli 2018). Additionally, other amino acid substitutions at this codon (p.Gly3076Arg, p.Gly3076Val) exhibit decreased HDR activity (Guidugli 2018), and p.Gly3076Val has been reported in a cohort of individuals with breast and/or ovarian cancer (Alemar 2017); however, the clinical significance of other variants at the same codon has not been conclusively determined. Still, based on available information, the p.Gly3076Glu variant is considered to be likely pathogenic. References: Alemar B et al. BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? PLoS One. 2017 Nov 21;12(11):e0187630. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. Guidugli L et al. Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet. 2018 Feb 1;102(2):233-248. Hahn SA et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003 Feb 5;95(3):214-21. Ikeda N et al. Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Int J Cancer. 2001 Jan 1;91(1):83-8. Li A et al. BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. Gynecol Oncol. 2018 Oct;151(1):145-152.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001290187 SCV001478277 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-09 criteria provided, single submitter curation Data used in classification: The frequency of this variant is 1/122,925 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (27.7) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified as likely pathogenic by 2 submitters on ClinVar; accredited USA diagnostic laboratories Ambry Genetics and GeneDx, both classified in 2017 (PP5_sup). Data not used in classification: There are additional reports of this variant in ClinVar (3), BIC (2), and BRCA2 LOVD (1).
Invitae RCV001290187 SCV001574109 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 3076 of the BRCA2 protein (p.Gly3076Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs80359187, ExAC 0.002%). This variant has been observed to segregate with breast and pancreatic cancer in an affected family (PMID: 12569143). It has also been reported in unrelated individuals affected with ovarian (PMID: 22711857, 30078507) or breast cancer (PMID: 11149425). ClinVar contains an entry for this variant (Variation ID: 52780). This variant has been reported to affect BRCA2 protein function (PMID: 29394989, 23108138, 19043619). Based on a multifactorial likelihood algorithm using functional and computational approaches, this variant has been determined to have a high probability of being pathogenic (PMID: 29394989). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000114069 SCV000147572 uncertain significance Breast-ovarian cancer, familial 2 1998-07-10 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.