ClinVar Genomic variation as it relates to human health

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.

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.

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.

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

BP4

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

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.