ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7878G>C (p.Trp2626Cys) (rs80359013)

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Total submissions: 20
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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 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 and ovarian cancer syndrome 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 2626 of the BRCA2 protein (p.Trp2626Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is present in population databases (rs80359013, ExAC <0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 22666503, 21203900, 20104584, 25085752, 11802209), and in patients affected with Fanconi anemia on the opposite chromosome of a second pathogenic BRCA2 variant (PMID: 16115142, 15070707, 21138478). This variant is also known in the literature as 8106G>C. ClinVar contains an entry for this variant (Variation ID: 38125). Experimental studies have shown that the complementation capability of this variant is absent or partially retained in BRCA2-deficient mouse-embryonic stem cells (PMID: 21719596, 25146914), and this variant affects sensitivity to DNA damaging agents as well as homology-directed repair activity (PMID: 21719596, 23108138). In addition, based on multifactorial likelihood algorithm using genetic, in silico, functional and statistical data, this variant has been determined to have a high probability of being deleterious (PMID: 17924331, 21990134). A history weighting algorithm using the severity of personal/family history of disease predicts that this variant might have a lower penetrance than that of typical BRCA2 pathogenic variants, but a penetrance estimate has not been determined due to the insufficient data (PMID: 25085752). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000163025 SCV000213513 pathogenic Hereditary cancer-predisposing syndrome 2020-02-12 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 2016-11-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031707 SCV000327755 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031707 SCV000488157 pathogenic Breast-ovarian cancer, familial 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 and 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 likely pathogenic not provided 2021-03-29 criteria provided, single submitter clinical testing Observed in patients with breast and other cancers, and in the compound heterozygous state in at least two children with Fanconi anemia (Wagner 2004, Barber 2005, Alter 2007, Capanu 2011, Konecny 2011, Kopic 2011, Borg 2010, Meyer 2012, Winter 2016, Gupta 2017); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); May confer lower breast and ovarian cancer risks than a typical BRCA2 pathogenic variant, but the cancer risks are unclear (Biswas 2011, Pruss 2014, Li 2020); Published functional studies are conflicting: variant showed impaired homologous recombination and sensitivity to PARP inhibitors; however, was able to rescue embryonic stem cell lethality with the rescued cells demonstrating reduced viability (Biswas 2011, Guidugli 2013, Stoepker 2015, Ikegami 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); 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, 21990134, 19043619, 24323938, 21520273, 25085752, 16825431, 18951461, 25782689, 27767231, 28315974, 15070707, 21138478, 26566862, 28866612, 21203900, 21990165, 29339979, 29394989, 28541631, 30257646, 30728895, 29988080, 30720243, 31853058, 30696104, 32444794, 29884841, 31263571, 30702160, 31825140, 32719484, 29625052, 32885271)
Department of Medical Genetics, Oslo University Hospital RCV000031707 SCV000605699 likely pathogenic Breast-ovarian cancer, familial 2 2016-12-16 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000045336 SCV000605791 pathogenic Hereditary breast and 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 Health, Inc RCV000163025 SCV000689074 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000482471 SCV001249493 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031707 SCV001429417 uncertain significance Breast-ovarian cancer, familial 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
Research and Development, ARUP Laboratories RCV001642462 SCV001854945 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031707 SCV000054314 likely pathogenic Breast-ovarian cancer, familial 2 2012-12-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031707 SCV000147208 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Division of Human Genetics,Medical University Innsbruck RCV000031707 SCV000212029 likely pathogenic Breast-ovarian cancer, familial 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.

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