ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7878G>C (p.Trp2626Cys) (rs80359013)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163025 SCV000213513 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Breast Cancer Information Core (BIC) (BRCA2) RCV000031707 SCV000147208 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000163025 SCV000689074 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-22 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
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
Division Human Genetics,Medical University Innsbruck RCV000031707 SCV000212029 likely pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
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
GeneDx RCV000482471 SCV000564795 likely pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7878G>C at the cDNA level, p.Trp2626Cys (W2626C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGC). This variant, also published as BRCA2 8106G>C using alternate nomenclature, has been 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). Various functional studies have demonstrated that this variant results in impaired BRCA2 function. Biswas et al. (2011) and Guidugli et al. (2013) independently showed that BRCA2 Trp2626Cys results in impaired homologous recombination, and Stoepker et al. (2015) found that this variant is sensitive to PARP inhibitors on studies of a cell line derived from a Fanconi anemia patient. Additionally, this variant was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. However, Pruss et al. (2014) indicated that this variant is a lower penetrance or hypomorphic allele based on a separate clinical history weighting algorithm. Biswas et al. (2011) also showed that this variant was able to rescue embryonic stem cell lethality with the rescued cells demonstrating reduced viability, further supporting the idea that BRCA2 Trp2626Cys is a hypomorphic allele. BRCA2 Trp2626Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA2 Trp2626Cys to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000045336 SCV000494423 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-10-14 criteria provided, single submitter clinical testing Variant Summary: BRCA2 c.7878G>A is a missense mutation that occurs at a conserved position and 5/5 in silico tools predict a damaging outcome. Functional studies carried out by at least 2 independent laboratories confirm these predictions, as W2626C is unable to fully complement ES cell lethality and DNA double-strand break repair function is impaired. The variant has been observed in multiple HBOC families. In addition, the possibility of a phenotypic association of this variant with Fanconi Anemia, when inherited in compound heterozygosity with a second pathogenic BRCA2 allele, also exists as evidenced by the patient reported in Wagner_2004. The observed allele frequency in controls, including the large and diverse ExAC cohort, is 2/121750, which is significantly less than the maximal expected allele frequency for a pathogenic HBOC or FA causative variant (1/1333 and 1/3055 respectively). Additionally, mutliple clinical diagnostic laboratories classify this variant as pathogenic/likely pathogenic. Taken together, this missense BRCA2 variant is probably a disease variant and has been classified as likely pathogenic until co-segregation data are available in multiple families.
Invitae RCV000045336 SCV000073349 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-27 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.
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482471 SCV000296697 pathogenic not provided 2016-11-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031707 SCV000054314 likely pathogenic Breast-ovarian cancer, familial 2 2012-12-19 no assertion criteria provided clinical testing

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