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

gnomAD frequency: 0.00001  dbSNP: rs41293511

Total submissions: 29

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, susceptibility to, 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 ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 2723 of the BRCA2 protein (p.Asp2723His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 11207042, 15290653, 16489001, 23961350, 24728189). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52515). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 15695382, 18607349, 23108138, 24013206, 25146914). This variant disrupts the p.Asp2723 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21990134). 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.
GeneDx	RCV000074555	SCV000108640	pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Observed in individuals with personal and family history of BRCA-related cancers, segregating with disease in at least 10 families (Pages et al., 2001; Goldgar et al., 2004; Mitra et al., 2008; Solano et al., 2012; Song et al., 2014; Shimelis et al., 2017); Published functional studies demonstrate a damaging effect: aberrant cellular localization, inability to rescue cell growth, and defective homology-directed repair activity (Wu et al., 2005; Farrugia et al., 2008; Kuznetsov et al., 2008; Jeyasekharan et al., 2013; Guidugli et al., 2018; Hart et al., 2019); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8395G>C; This variant is associated with the following publications: (PMID: 24728189, 15695382, 18451181, 18182994, 25447315, 23961350, 25085752, 11207042, 15026808, 29922827, 28888541, 21702907, 22505045, 24323938, 25146914, 25782689, 24013206, 15290653, 19043619, 23108138, 18607349, 16489001, 27225637, 20223037, 26775038, 28283652, 28324225, 26586665, 28008555, 27550963, 26681312, 28158555, 29394989, 29446198, 29988080, 30322717, 30309722, 31263054, 32444794, 30696104, 34399810, 33609447, 30787465, 28184943, 35736817, 35464868, 12228710, 29884841, 33964450, 21990134, 35665744)
Ambry Genetics	RCV000131674	SCV000186710	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-07	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	In the published literature, this variant has been reported in individuals with breast, ovarian, and prostate cancer (PMIDs: 18182994 (2008), 18451181 (2008), 19043619 (2008), 16489001 (2006)), and to segregate with breast and/or ovarian cancer in multiple families (PMIDs: 16489001 (2006), 15290653 (2004)). In addition, this variant has been reported to have a deleterious effect on BRCA2 protein function in numerous studies (PMIDs: 29394989 (2018), 25146914 (2014), 19043619 (2008), 16978908 (2007), 15695382 (2005)). 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 pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077429	SCV000327825	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077429	SCV000489715	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-11-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131674	SCV000537677	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-05	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 disrupts BRCA2 function, including homology-directed DNA repair activity (PMID: 15695382, 18607349, 19043619, 23108138, 25146914). This variant has been reported in over a dozen individuals affected with breast and/or ovarian cancer (PMID: PMID: 11207042, 23961350, 24052750, 24728189, 33471991; Leiden Open Variation Database DB-ID BRCA2_000290) 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	RCV000074555	SCV000602850	pathogenic	not provided	2023-05-08	criteria provided, single submitter	clinical testing	The BRCA2 c.8167G>C; p.Asp2723His variant (rs41293511), is reported in the literature in several individuals affected with breast and ovarian cancer (Goldgar 2004, Pages 2001, Wu 2005). Functional analyses of BRCA2 protein carrying this variant demonstrate centrosome amplification and aberrant subcellular localization resulting in defective DNA repair on exposure to gamma irradiation and mitomycin-c (Carvalho 2007, Goldgar 2004, Wu 2005). Furthermore, BRCA2 Asp2723His variant has been shown to interfere with the nuclear localization of RAD51, another key DNA repair protein (Jeyasekharan 2013). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 52515). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.932). Several alternative changes at this amino acid location (p.Asp2723Gly, p.Asp2723Ala, p.Asp2723Val) that are predicted to be pathogenic have also been reported in patients with breast and ovarian cancer (Guidugli 2018). Based on available information, the p.Asp2723His variant is considered to be pathogenic. References: Carvalho MA et al. Functional assays for BRCA1 and BRCA2. Int J Biochem Cell Biol. 2007;39(2):298-310. Goldgar DE et al. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet. 2004 Oct;75(4):535-44. 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. Jeyasekharan AD et al. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat Struct Mol Biol. 2013 Oct;20(10):1191-8. Pages S et al. Screening of male breast cancer and of breast-ovarian cancer families for BRCA2 mutations using large bifluorescent amplicons. Br J Cancer. 2001 Feb;84(4):482-8. Wu K et al. Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res. 2005 Jan 15;65(2):417-26.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045436	SCV000695133	pathogenic	Hereditary breast 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, susceptibility to, 2	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077429	SCV000744535	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-09-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170973	SCV001333633	pathogenic	Breast and/or ovarian cancer	2023-06-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045436	SCV001653096	pathogenic	Hereditary breast 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.
Revvity Omics, Revvity	RCV000074555	SCV002019208	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045436	SCV002025844	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000074555	SCV002585444	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	BRCA2: PM1:Strong, PS3, PM2, PP1, PS4:Supporting, BP1
Baylor Genetics	RCV003473415	SCV004211788	pathogenic	Familial cancer of breast	2023-10-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904999	SCV004725118	pathogenic	BRCA2-related condition	2023-10-18	criteria provided, single submitter	clinical testing	The BRCA2 c.8167G>C variant is predicted to result in the amino acid substitution p.Asp2723His. This variant has been documented in multiple individuals with breast and ovarian cancer and has been shown to cause defective DNA repair (Goldgar et al. 2004. PubMed ID: 15290653; Karchin et al. 2008. PubMed ID: 19043619; Guidugli et al. 2013. PubMed ID: 23108138; Guidugli et al. 2018. PubMed ID: 29394989). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. It is interpreted as pathogenic in ClinVar, including by the ENIGMA expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/52515/). This variant is interpreted as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000077429	SCV004845616	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-08	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 disrupts BRCA2 function, including homology-directed DNA repair activity (PMID: 15695382, 18607349, 19043619, 23108138, 25146914). This variant has been reported in over a dozen individuals affected with breast and/or ovarian cancer (PMID: PMID: 11207042, 23961350, 24052750, 24728189, 33471991; Leiden Open Variation Database DB-ID BRCA2_000290) 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.
Sharing Clinical Reports Project (SCRP)	RCV000077429	SCV000109227	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077429	SCV000147287	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 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, susceptibility to, 2		no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001391219	SCV001593135	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000074555	SCV001951051	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045436	SCV001977037	pathogenic	Hereditary breast ovarian cancer syndrome	2021-09-27	no assertion criteria provided	clinical testing