Submissions for variant NM_000059.4(BRCA2):c.8378G>A (p.Gly2793Glu)

dbSNP: rs80359083

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045500	SCV000073513	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-08	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 2793 of the BRCA2 protein (p.Gly2793Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 38157). 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: 23108138, 29394989, 29884841). This variant disrupts the p.Gly2793 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12442275, 15889636, 16030099, 19043619, 23108138, 23233716, 25085752, 25777348). 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.
Ambry Genetics	RCV000165807	SCV000216554	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-06	criteria provided, single submitter	clinical testing	The p.G2793E variant (also known as c.8378G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8378. The glycine at codon 2793 is replaced by glutamic acid, an amino acid with similar properties. This alteration was found to produce exon 19 skipping; however, the majority of transcript produced by this alteration is wildtype (Acedo A et al. Breast Cancer Res. 2012 May;14:R87). This amino acid substitution was shown to be defective in a homology directed repair assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468). Based on internal structural analysis, this alteration is predicted to disrupt binding to DSS1 and is more destabilizing to the local structure than other known pathogenic variants (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165807	SCV000689121	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 2793 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 results in impaired homology-directed DNA repair (PMID: 23108138, 29394989, 33609447) and abnormal splicing (PMID: 22632462). This variant has been reported in 3 individuals affected with breast or ovarian cancer (PMID: 33672545, Lovejoy 2018, Color internal data). Another variant at this amino acid (Gly2793Arg) has been classified as pathogenic (ClinVar Variant ID: 52569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000679191	SCV000805777	likely pathogenic	not provided	2024-04-12	criteria provided, single submitter	clinical testing	A hybrid minigene functional assay has demonstrated skipping of exon 19 in the BRCA2 gene from this variant (Acedo et al. 2012. PubMed ID: 22632462). Another functional study shows that this variant causes reduced protein function compared to wildtype (Guidugli et al. 2012. PubMed ID: 23108138). Alternate missense changes at this amino acid (p.Gly2793Arg, p.Gly2793Val) are classified as pathogenic (Richardson et al. 2021. PubMed ID: 33609447). Although the classifications in ClinVar range from uncertain to pathogenic, the vast majority of recent entries are likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38157/). This variant has not been observed in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000045500	SCV001429660	pathogenic	Hereditary breast ovarian cancer syndrome	2019-02-14	criteria provided, single submitter	clinical testing	Data used in classification: Case control comparison of UK familial cases against ethnically matched population data (5/25,773 in familial UK cases against 0/56,856 GNOMAD NFE controls) 2-sided Fishers exact: pexact= 0.0030 (PS4_strong). Absent in the remainder of the gnomAD population (PM2_mod). This variant is predicted deleterious on AlignGVGD (class:C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging), CADD (29.8), Revel [0-1]: 0.916, Gavin class: Pathogenic, (confidence: genomewide) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay DNA Binding Domain assay (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of P=1.0 (PS3_strong). Data not used in classification: There are additional reports of this variant in ClinVar (5), DMuDB (1), BIC(4), and BRCA2 LOVD(1). 5 Classifications on ClinVar as uncertain. Ambry classification: likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679191	SCV001469720	likely pathogenic	not provided	2024-02-21	criteria provided, single submitter	clinical testing	The BRCA2 c.8378G>A (p.Gly2793Glu) variant has been reported in the published literature in an elderly individual with male breast cancer (PMID: 33672545 (2021), and in an individual with female breast cancer who carried a second BRCA2 missense variant (Lovejoy et al. Austin J Cancer Clin Res (2018) 5(1):1082). The c.8378G>A (p.Gly2793Glu) variant has been predicted to be likely deleterious based on protein likelihood ratio modeling (PMID: 19043619 (2008)), and experimental studies indicate it has deleterious effects on BRCA2 homology-directed DNA repair activity (PMIDs: 23108138 (2013), 29394989 (2018), 29884841 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
GeneDx	RCV000679191	SCV003798671	likely pathogenic	not provided	2023-01-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly reduced homologous recombination DNA-repair activity (Guidugli et al., 2013; Guidugli et al., 2018; Iversen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer (Lovejoy et al., 2018; Butz et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8606G>A; This variant is associated with the following publications: (PMID: 23108138, 24323938, 32623769, 25382762, 33609447, 33672545, 32170000, 19043619, 22632462, 12228710, 29884841, 32719484, 35665744, 10923033, 29394989)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045500	SCV003933885	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8378G>A (p.Gly2793Glu) results in a non-conservative amino acid change located in the BRCA2 OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes (gnomAD). c.8378G>A has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer (example: Butz_2021). The variant of interest has been functionally assessed for effect on splicing and showed that it did influence exon 19 splicing (~15%), with the predominant product being the wild type BRCA2 protein (~85%) (Acedo_2012), additionally, the variant of interest was shown to significantly affect homology-directed repair activity (example: Guidugli_2013, Richardson_2021). Other variants affecting the same amino acid residue is classified pathogenic/likely pathogenic in ClinVar (CV ID 52569, 38158). This suggests that this residue may play a critical role in normal protein function. The following publications have been ascertained in the context of this evaluation (PMID: 22632462, 33672545, 32719484, 23108138, 24323938, 19043619, 33609447). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and pathogenic/likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003473219	SCV004210446	likely pathogenic	Familial cancer of breast	2022-11-18	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000045500	SCV004231821	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	curation	. According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): LOF in HRD-Assay (Richardson et al., (PMID:33609447) Own RNA-Analysis in patient derived blood sample revealed biallelic expression of variant in WT-transcript, PM2 (supporting pathogenic): not in gnomAD, PP3 (supporting pathogenic): CADD:29.5 REVEL: 0.916 HCI prior:0.81 BayesDEL:0.583972 spliceAI:BRCA2: 0.05
All of Us Research Program, National Institutes of Health	RCV000031740	SCV004845649	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 2793 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 results in impaired homology-directed DNA repair (PMID: 23108138, 29394989, 33609447) and abnormal splicing (PMID: 22632462). This variant has been reported in 3 individuals affected with breast or ovarian cancer (PMID: 33672545, Lovejoy 2018, Color internal data). Another variant at this amino acid (Gly2793Arg) has been classified as pathogenic (ClinVar Variant ID: 52569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031740	SCV000054347	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-07-08	flagged submission	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031740	SCV000147350	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-07-07	flagged submission	clinical testing
BRCAlab, Lund University	RCV000031740	SCV004243813	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing