Submissions for variant NM_000059.4(BRCA2):c.9227G>A (p.Gly3076Glu)

dbSNP: rs80359187

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216816	SCV000274761	pathogenic	Hereditary cancer-predisposing syndrome	2025-02-03	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	2024-01-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9455G>A; This variant is associated with the following publications: (PMID: 19043619, 11149425, 19064968, 20195775, 18437078, 12569143, 23108138, 26402249, 28324225, 24323938, 22711857, 29161300, 29394989, 26295337, 12228710, 22632462, 29884841, 30113427, 35736817, 35665744, 35563554, 33609447, 34906479, 30078507, 29922827, 30040829, 28888541)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000221088	SCV000296594	pathogenic	not provided	2024-05-08	criteria provided, single submitter	clinical testing	The BRCA2 c.9227G>A (p.Gly3076Glu) variant has been reported in the published literature in individuals with breast and/or ovarian cancer or pancreatic cancer (PMIDs: 11149425 (2001), 12569143 (2003), 20195775 (2010), 22711857 (2012), 28324225 (2017), 28888541 (2017), 30078507 (2018), and 30040829 (2018)). Experimental studies showed that this variant results in decreased activity in homology-directed recombination (HDR) assays (PMIDs: 23108138 (2013), 29394989 (2018), 29884841 (2019), 33609447 (2021), and 35736817 (2022)). In addition, a multifactorial likelihood analysis predicted the variant to be likely deleterious (PMID: 19043619 (2008)). The frequency of this variant in the general population, 0.000004 (1/250980 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000221088	SCV001473600	likely pathogenic	not 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 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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001290187	SCV001574109	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 3076 of the BRCA2 protein (p.Gly3076Glu). This variant is present in population databases (rs80359187, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast, ovarian, and/or pancreatic cancer (PMID: 11149425, 12569143, 22711857, 30078507). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52780). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 19043619, 23108138, 29394989). This variant disrupts the p.Gly3076 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23108138, 29394989, 30254663, 32814805). 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.
Genetics and Molecular Pathology, SA Pathology	RCV000114069	SCV002761887	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-04-03	criteria provided, single submitter	clinical testing	The BRCA2 c.9227G>A variant is classified as Likely Pathogenic (PS3, PM2, PP5) The BRCA2 c.9227G>A variant is a single nucleotide change the BRCA2 gene, which is predicted to change the amino acid glycine at position 3076 in the protein to glutamic acid. The variant is rare in population databases (PM2). not in FLOSSIES - very rare 1 in 250000 alleles. Well-established functional studies show a deleterious effect of this variant (PS3). Invariantly conserved (to Class Echinodermata; Strongylocentrotus purpuratus) and in known functional domain Yang et al., 2002 PMID:12228710. no impact on splicing The variant has been reported in dbSNP (rs80359187) and has been reported with Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 52780). It has not been reported in HGMD.
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760360	SCV005368420	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-08-21	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM2_SUP,PP3
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114069	SCV000147572	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1998-07-10	flagged submission	clinical testing
Counsyl	RCV000114069	SCV000489258	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-11	flagged submission	clinical testing