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

dbSNP: rs28897743

Total submissions: 33

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, susceptibility to, 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 ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2336 of the BRCA2 protein (p.Arg2336His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer, Fanconia anemia, and acute myelogenous leukemia (PMID: 12065746, 16115142, 22430266, 22486713, 25395318, 26968956). This variant is also known as 7235G>A. ClinVar contains an entry for this variant (Variation ID: 38077). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 27124784). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exons 12 and/or 13 and introduces a premature termination codon (PMID: 16792514, 20215541, 22505045; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.7007G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9150172, 9536098, 17576681, 20960228, 21548014, 22399190, 22505045). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131031	SCV000185961	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	clinical testing	The c.7007G>A pathogenic mutation (also known as p.R2336H), located in coding exon 12 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7007. This changes the amino acid at codon 2336 from arginine to histidine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This mutation has been identified in multiple families affected with breast and/or ovarian cancer (Claes K et al Br .J. Cancer. 2004 Mar;90:1244-51; Machackova E et al. BMC Cancer. 2008 May;8:140; Ahmad J et al. Clin. Genet. 2012 Dec;82:594-8; Coppa A et al. Breast Cancer Res. Treat. 2014 Dec;148:629-35; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620; Fanale D et al. Cancers (Basel) 2020 Aug;12(9)). This mutation has also been reported in both a homozygous and compound heterozygous state in individuals diagnosed with Fanconi Anemia and AML (Barber LM et al. Br. J. Haematol. 2005 Sep;130:796-7; Ghazwani Y et al. Cancer Genet 2016 Apr;209(4):171-6). In addition, the c.7007G>A mutation has been shown to result in a deletion of exon 13 from the mRNA transcript, causing a frameshift and a premature stop codon in exon 14 (Ambry internal data; Farrugia D et al. Cancer Res. 2008 May;68:3523-31; Thomassen M et al. Genet. Test. 2006 Summer;10:116-20; Biswas K et al. Blood. 2011 Sep;118:2430-42; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Houdayer C et a. Hum. Mutat. 2012 Aug;33:1228-38). A multifactorial likelihood ratio analysis that included co-segregation, tumor pathology, co-occurrence and family history data determined this alteration to be pathogenic (Parsons MT et al. Hum Mutat 2019 09;40(9):1557-1578). Of note, this alteration is also designated as 7235G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
GeneDx	RCV000174440	SCV000210411	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing	Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing, producing transcripts skipping exons 13 and exons 12-13, which lead to protein truncation or nonsense-mediated decay (Thomassen et al., 2006; Sanz et al., 2010; Biswas et al., 2011; Mesman et al., 2020); Observed in individuals with personal or family history of BRCA2-related cancers (Martin et al., 2001; Coppa et al., 2014; Bu et al., 2016; Lang et al., 2017; Kowalik et al., 2018; Fanale et al., 2020); Observed in the compound heterozygous or homozygous state in individuals with Fanconi anemia (Howlett et al., 2002; Degrolard-Courcet et al., 2014; Ghazwani et al., 2016); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing.; Also known as 7235G>A; This variant is associated with the following publications: (PMID: 16115142, 15645491, 25556971, 27884173, 28477318, 28541631, 11304778, 29310832, 34290354, 32438681, 15026808, 28888541, 33754277, 31558676, 31921681, 29176636, 20215541, 18489799, 22505045, 22486713, 24301060, 21719596, 18451181, 16825431, 16792514, 25395318, 26968956, 27082205, 28294317, 28503720, 28476184, 17924331, 29297111, 28152038, 29907814, 28724667, 25186627, 29084914, 29387975, 30040829, 29565420, 15356654, 12065746, 32854451, 32398771, 33293522, 30214071, 29446198, 30825404, 31065452, 31131967, 34026625, 31825140, 31589614, 32719484, 32853339, 30787465, 35886069, 35494038, 34515413, 34178674, 35382848)
Eurofins Ntd Llc (ga)	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	2021-09-16	criteria provided, single submitter	clinical testing	In the published literature, in vitro functional studies have shown that this variant has a deleterious effect on BRCA2 mRNA splicing and causes the synthesis of BRCA2 mRNA without exons 12 and/or 13 (PMIDs: 22505045 (2012), 16792514 (2006)). This variant has also been reported in affected individuals with breast and/or ovarian cancer as well as Fanconi anemia (PMIDs: 30825404 (2019), 25395318 (2014), 18489799 (2008), 12065746 (2002)). 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	RCV000031659	SCV000327565	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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
Counsyl	RCV000031659	SCV000677695	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-06-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131031	SCV000689020	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This variant alters the conserved, last nucleotide c.G of exon 13 of the BRCA2 gene and is predicted to affect RNA splicing. This variant is also known as p.Arg2336His based on predicted change at the protein level. RNA studies have shown that this variant causes the out-of-frame skipping for exon 13 and exons 12 and 13 in carrier RNA (PMID: 16792514, 18489799, 20215541, 22505045). This variant has also been shown to poorly rescue BRCA2 deficiency and confer hypersensitivity to DNA damaging agents in mouse embryonic stem cells (PMID: 21719596). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 16792514, 20215541, 22505045, 30192042), and the variant is reported to cosegregate with disease with a likelihood ratio of 48.5651 (PMID: 31131967). This variant has also been observed in individuals affected with Fanconi anemia in compound heterozygosity with a pathogenic BRCA2 variant (PMID: 12065746, 24301060) or in homozygosity (PMID: 26968956). 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 Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045112	SCV000695022	pathogenic	Hereditary breast 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031659	SCV000744505	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000031659	SCV001139167	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000174440	SCV001159457	pathogenic	not provided	2023-09-14	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, Fanale 2020, Ghazwani 2016). This variant is also reported in ClinVar (Variation ID: 38077) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). 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: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ 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. PMID: 22486713. 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. PMID: 21719596. 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. PMID: 25395318. Fanale D et al. Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2. Cancers (Basel). 2020 Aug 25;12(9):2415. PMID: 32854451. Ghazwani Y et al. Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients. Cancer Genet. 2016 Apr;209(4):171-6. PMID: 26968956. 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. PMID: 22505045. 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. PMID: 20215541.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000031659	SCV001368474	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-11-06	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP1.
Sema4, Sema4	RCV000131031	SCV002536290	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496486	SCV002806006	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	2021-10-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000174440	SCV003814338	pathogenic	not provided	2022-07-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031659	SCV003932753	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A known pathogenic mutation was detected in the BRCA2 gene. This sequence change replaces arginine with histidine at codon 2336 of the BRCA2 protein (p.Arg2336His). RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer, Fanconi anemia, and acute myeloid 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) with 26 submissions, all of which describe it as pathogenic, 3 stars, reviewed by expert panel. In silico predictions show this variant to pathogenic (PMID: 27124784). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16792514, 22505045, 20215541). Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9150172, 22399190, 20960228, 21548014, 17576681, 9536098, 22505045). Therefore, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000174440	SCV004226610	pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing	PP5, PM2, PM3, PS3, PS4_moderate
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000031659	SCV004804680	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-03-17	criteria provided, single submitter	research
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, susceptibility to, 2	2012-10-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031659	SCV000146991	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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 ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000174440	SCV000592088	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Arg2336His variant has been previously reported in the literature and by our laboratory. It has been reported in the literature in 7 out of 12688 proband chromosomes (Barber 2005, Easton 2007, Machackova 2008, Sanz 2010) in individuals with hereditary breast cancer, male breast cancer and AML. It has also been reported by our laboratory in one individual who met criteria for hereditary breast and ovarian cancer testing. The p.Arg2336His variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. It is listed in dbSNP database (ID#: rs28897743), but no frequency information was provided. This variant was shown to induce aberrant splicing resulting in the deletion of the 70-bp exon 13 from the mRNA and causes a frameshift and premature stop codon in exon 14 (Thomassen 2006). Mutations causing frameshift and truncation of the BRCA2 protein have been shown to be clinically important, and loss of function of the BRCA2 gene represents an established disease mechanism in hereditary breast cancer patients. In addition, functional assays have shown a reduction in the full-length transcript production compared with wild-type cells, hypersensitivity to various DNA damaging agents, defect in HR-mediated DNA repair and an increase in genomic instability has been reported (Biswas 2011, Farrugia 2008). In summary, based on the above information, this variant is classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031659	SCV000733290	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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
CZECANCA consortium	RCV000735595	SCV001451880	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000174440	SCV001951528	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031659	SCV002588906	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000009923	SCV003927872	pathogenic	Fanconi anemia complementation group D1	2023-04-01	no assertion criteria provided	clinical testing