ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1466C>G (p.Ser489Cys)

gnomAD frequency: 0.00001  dbSNP: rs587782535
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131739 SCV000186780 likely benign Hereditary cancer-predisposing syndrome 2019-11-20 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000198082 SCV000254169 likely benign Hereditary breast ovarian cancer syndrome 2024-01-03 criteria provided, single submitter clinical testing
GeneDx RCV000586148 SCV000279251 uncertain significance not provided 2018-07-31 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1466C>G at the cDNA level, p.Ser489Cys (S489C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 1694C>G. This variant has been identified in at least five woman with breast or ovarian cancer (Soegaard 2008, Borg 2010, Carney 2010). BRCA2 Ser489Cys was observed at an allele frequency of 0.01% (14/109,108) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser489Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586148 SCV000296696 uncertain significance not provided 2021-08-26 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131739 SCV000683426 likely benign Hereditary cancer-predisposing syndrome 2021-06-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586148 SCV000694541 uncertain significance not provided 2016-04-01 criteria provided, single submitter clinical testing Variant Summary: The c.1466C>G variant in BRCA2 gene involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.007%, exclusively in individuals of European descent (0.01%), which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been reported in affected individuals in the literature, without strong evidence for causality. Multiple reputable clinical labs have classified the variant as a VUS. The variant was found to co-occur with a known pathogenic variant, c.5341delG (p.Glu1781fsX12) in BRCA1 gene. Taking all evidence together, this variant has been classified as a VUS until additional evidence becomes available.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170456 SCV001333036 uncertain significance Breast and/or ovarian cancer 2019-03-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000586148 SCV001474312 uncertain significance not provided 2019-08-22 criteria provided, single submitter clinical testing The BRCA2 c.1466C>G; p.Ser489Cys variant (rs587782535) is reported in the literature in individuals affected with breast or ovarian cancer (Borg 2010, Carney 2010, Sinilnikova 2006, Soegaard 2008), but also in healthy controls (Capanu 2011). This variant is reported in ClinVar (Variation ID: 142547), and is found in the Finnish European population with an allele frequency of 0.014% (15/111120 alleles) in the Genome Aggregation Database. The serine at codon 489 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Ser489Cys variant is uncertain at this time. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 31(3):E1200-40. Capanu M et al. Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. Genet Epidemiol. 2011 Jul;35(5):389-97. Carney ME et al. Detection of BRCA1 and BRCA2 mutations in a selected Hawaii population. Hawaii Med J. 2010 Nov;69(11):268-71. Sinilnikova OM et al. BRCA1 and BRCA2 mutations in breast and ovarian cancer syndrome: reflection on the Creighton University historical series of high risk families. Fam Cancer. 2006;5(1):15-20. Soegaard M et al. BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark. Clin Cancer Res. 2008 14(12):3761-7.
Sema4, Sema4 RCV000131739 SCV002533235 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-23 criteria provided, single submitter curation
University of Washington Department of Laboratory Medicine, University of Washington RCV000131739 SCV003851411 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003321517 SCV004027403 likely benign not specified 2024-02-06 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000586148 SCV004226417 uncertain significance not provided 2022-04-04 criteria provided, single submitter clinical testing BP4
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000586148 SCV001548856 uncertain significance not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535543 SCV001749518 not provided Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 06-26-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
BRCAlab, Lund University RCV003493458 SCV004244219 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2020-03-02 no assertion criteria provided clinical testing

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