Submissions for variant NM_000059.4(BRCA2):c.7878G>C (p.Trp2626Cys)

gnomAD frequency: 0.00001  dbSNP: rs80359013

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031707	SCV000244475	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	RCV000045336	SCV000073349	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 2626 of the BRCA2 protein (p.Trp2626Cys). This variant is present in population databases (rs80359013, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and Fanconi anemia (PMID: 11802209, 15070707, 16115142, 20104584, 21138478, 21203900, 22666503, 25085752). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38125). 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: 17924331, 21990134). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 17924331, 21719596, 21990134, 23108138, 25146914). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000163025	SCV000213513	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	The p.W2626C pathogenic mutation (also known as c.7878G>C), located in coding exon 16 of the BRCA2 gene, results from a G to C substitution at nucleotide position 7878. The tryptophan at codon 2626 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been described in families with phenotypes consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Meindl A et al. Int. J. Cancer 2002 Feb;97:472-80; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Konecny M et al. Breast Cancer Res. Treat. 2011 Feb;126:119-30; Meyer P et al. PLoS ONE 2012;7:e38361; Winter C et al. Ann. Oncol. 2016 Aug;27:1532-8; Polsler L et al. Eur. J. Hum. Genet. 2016 Feb;24:258-62). This variant has also been identified in two unrelated patients with Fanconi Anemia (Wagner JE et al. Blood. 2004 Apr;103:3226-9; Kopic S et al. Acta Paediatr. 2011 May;100:780-3). In one of these patients, this alteration was confirmed to be in trans with a frameshift mutation (Wagner JE et al. Blood. 2004 Apr;103:3226-9). Functional assays evaluating homology-directed DNA break repair (HDR), embryonic stem cell rescue viability, susceptibility to DNA damaging agents, chromosomal aberration, and RAD51 foci have all indicated deficient function in BRCA2 p.W2626C mutants (Biswas K et al. Blood. 2011 Sep;118:2430-42; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Hendriks G et al. Hum. Mutat. 2014 Nov;35:1382-91; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Mesman RLS et al. Genet. Med., 2018 Jul;). However, one paper describes this as a hypomorphic variant based on a history weighting algorithm (Pruss D et al. Breast Cancer Res. Treat., 2014 Aug;147:119-32). 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482471	SCV000296697	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251276 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant is described as a pathogenic variant with reduced penetrance, carrying a lower breast cancer risk than other BRCA2 pathogenic variants (PMID: 34906479 (2022)). It has been reported in individuals or families with breast cancer (PMIDs: 34680878 (2021), 34906479 (2022), 30728895 (2019), 30257646 (2018), 29339979 (2018), 27194814 (2016), 26014432 (2015), 22666503 (2012), 21203900 (2011)) or prostate cancer (PMID: 32853339 (2021)). This variant has also been reported in trans with a second pathogenic BRCA2 variant in patients with Fanconi anemia (PMIDs: 21138478 (2011), 15070707 (2004)). Published functional studies indicate that this variant impairs BRCA2 protein activity (PMIDs: 33978741 (2021), 32444794 (2020), 30696104 (2019), 29884841 (2019), 29394989 (2018), 29988080 (2018), 25146914 (2014), 23108138 (2013), 21719596 (2011)). Based on the available information, this variant is classified as pathogenic with reduced penetrance.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031707	SCV000327755	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031707	SCV000488157	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045336	SCV000494423	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-28	criteria provided, single submitter	clinical testing	BRCA2 c.7878G>C (p.Trp2626Cys) results in a non-conservative amino acid change in the helical domain (IPR015252). Five in-silico tools predict a damaging effect. Observed at a frequency of 7.9e-06 in 251676 control chromosomes. Reported in individuals with Hereditary Breast and Ovarian Cancer (PMID's listed) and in trans with another BRCA2 variant (2041insA) in individuals with Fanconi Anemia (PMID's listed and BIC database). Several publications report experimental evidence demonstrating an inability to complement the cell lethal phenotype induced by loss of endogenous mouse BRCA2 (PMID's listed). One expert panel (ENIGMA) and ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=6)/likely pathogenic (n=5). Based on the evidence outlined above, the variant was re-classified as pathogenic.
GeneDx	RCV000482471	SCV000564795	pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	Multifactorial studies suggest this variant is associated with breast and ovarian cancer, but may confer lower risks than typical BRCA2 pathogenic variants (Biswas et al., 2011; Lindor et al., 2012; Pruss et al., 2014; Li et al., 2020; Li et al., 2022); Published functional studies demonstrate a damaging effect: impaired homologous recombination and sensitivity to PARP inhibitors (Biswas et al., 2011; Stoepker et al., 2015; Guidugli et al., 2018; Ikegami et al., 2020; Lee et al., 2021; Iversen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 8106G>C; This variant is associated with the following publications: (PMID: 23108138, 17924331, 22666503, 20104584, 27194814, 29478780, 31409081, 29446198, 30291343, 12228710, 25146914, 25583207, 16115142, 21719596, 19043619, 24323938, 21520273, 25085752, 16825431, 18951461, 25782689, 27767231, 28315974, 21138478, 26566862, 28866612, 21203900, 21990165, 29339979, 28541631, 30257646, 30728895, 29988080, 30720243, 31853058, 30696104, 32444794, 29884841, 31263571, 30702160, 31825140, 32719484, 29625052, 32885271, 32853339, 30787465, 32295079, 34906479, 34680878, 29394989, 21990134, 15070707, 29922827, 31794323, 35665744, 33978741, 34308104)
Department of Medical Genetics, Oslo University Hospital	RCV000031707	SCV000605699	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-12-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045336	SCV000605791	pathogenic	Hereditary breast ovarian cancer syndrome	2017-07-20	criteria provided, single submitter	clinical testing	The p.Trp2626Cys variant in BRCA2 has been reported in >16 individuals with BRCA 2-associated cancers (Han 2006, Petersen 2016, Breast Cancer Information Core). This variant has been identified in 2/66726 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359013) . However, this frequency is low enough to be consistent with the frequency of h ereditary breast and ovarian cancer (HBOC) in the general population. In vitro f unctional studies provide some evidence that the p.Trp2626Cys may impact protein function (Hendriks 2014). Computational prediction tools and conservation analy sis suggest that the p.Trp2626Cys variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In addition, this variant was classified as Pathogenic on Aug 10, 2016 by the ClinGen-approved EN IGMA expert panel (ClinVar SCV000244475.1). In summary, although additional stud ies are required to fully establish its clinical significance, the p.Trp2626Cys variant is likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000163025	SCV000689074	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 2626 in the DNA binding 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 showed loss of function in homology-directed repair and DNA damage response assays and the complementation of Brca2-deficient mouse embryonic stem cells, and it impaired nuclear localization of BRCA2 protein (PMID: 21719596, 23108138, 25146914, 29884841, 29988080, 33978741). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11802209, 20104584, 21203900, 22666503, 26014432, 27194814) and this variant also has been detected in a breast cancer case-control meta-analysis in 7/60466 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000238). In a study of 34 families, this variant has shown reduced penetrance and lower risk of breast cancer compared with other pathogenic variants in the BRCA1 and BRCA2 genes (PMID: 34906479). This variant has also been observed in two unrelated, biallelic individuals affected with Fanconi anemia, who were compound heterozygous with pathogenic variant in the same gene (PMID: 15070707; 16115142, 21138478), indicating that this variant contribute to disease. This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic with reduced penetrance.
CeGaT Center for Human Genetics Tuebingen	RCV000482471	SCV001249493	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BRCA2: PS3, PM1, PS4:Moderate, PM2:Supporting, PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031707	SCV001429417	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-01-11	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000482471	SCV001447631	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000482471	SCV002551646	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288525	SCV002579195	pathogenic	Familial cancer of breast	2022-04-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504846	SCV002816654	likely 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	2022-02-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000482471	SCV003814449	pathogenic	not provided	2022-07-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002288525	SCV004213635	pathogenic	Familial cancer of breast	2023-08-26	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031707	SCV000054314	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-12-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031707	SCV000147208	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000031707	SCV000212029	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-11	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001271059	SCV001451881	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357728	SCV001553281	likely pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Trp2626Cys variant was identified in 4 of 7208 proband chromosomes (frequency: 0.0006) from individuals or families with contralateral and unilateral breast cancers, and was not identified in 2996 control chromosomes from healthy individuals (Borg 2010 PMID:20104584, Pruss 2014 PMID:25085752, Capanu 2011 PMID:21520273, Petersen 2016 PMID:26733283). The variant has also been identified in at least one patient with Fanconi anemia who also harboured a BRCA2 frameshift pathogenic variant (Stoepker 2015 PMID:25583207). In a study done to classify unknown variants, the variant was submitted to web-based algorithms using Align-GVGD, Grantham Variation and Grantham Deviation scores and found to be class (C65) of substitutions, which is most likely to interfere with function and was scored as possibly deleterious (Borg 2010 PMID:20104584). Furthermore studies classified the variant as deleterious based on a loss of DNA repair function identified through function studies (Biswas 2011 PMID:21719596, Guidugli 2013 PMID: 23108138, Hendriks 2014 PMID:25146914). The variant was shown to be sensitive to PARP inhibitors when present in a cell line derived from a patient with Fanconi anemia (Stoepker 2015). In addition Lindor et al. 2011 (PMID:21990134) determined the variant to be pathogenic (48.14 possibility of causality) when they weighted together segregation data, co-occurrence with pathogenic variants, personal and family history, and tumor pathology. However the above study by Biswas et al. 2011 demonstrated that the variant may be hypomorphic as it was able to recuse lethality in embryonic stem cells (notably in a similar experiment in the Hendrick et al. study the variant did not rescue lethality), and Pruss et al. 2014 also classified the variant as hypomorphic based on clinic history weighting algorithm. The variant was identified in dbSNP (ID: rs80359013 “With Pathogenic Allele”, in 1000 Genomes Project in 2 of 100000 chromosomes (frequency: 0.00002). The variant was also identified in the Exome Aggregation Consortium database (released Mar 14, 2016) in 2 of 121350 chromosomes (frequency: 0.00002) from a population of 2 of 66726 (0.00003) of European (Non-Finnish) alleles, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified in GeneInsight-COGR by Trillum Health Partners 1x as Class 5, in Clinvar (pathogenic by ENIGMA, Quest, CIMBA, Counsyl, LMM, and Invitae, AND as likely pathogenic by LabCorp, GeneDx, Oslo University, Ambry, SCRP, and Medical University Innsbruck as well as Uncertain Significance by BIC). The variant is further identified in the BIC database 14X with unknown clinical importance, in the ARUP Laboratories BRCA Mutations Database 1x as definitely pathogenic, in the Fanconi Anemia Mutation Database (LOVD) 2x as predicted deleterious and 1x with reduced complementation. The variant was not listed in the COSMIC, MutDB, and UMD databases. The p.Trp2626 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
CZECANCA consortium	RCV003128132	SCV003804352	pathogenic	Uterine corpus cancer	2023-02-21	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031707	SCV004243787	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing