ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9872C>G (p.Ser3291Cys) (rs200210279)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129292 SCV000184053 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129292 SCV000684096 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000480317 SCV000570133 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9872C>G at the cDNA level, p.Ser3291Cys (S3291C) 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 10100C>G. This variant was observed in at least two individuals with triple negative breast cancer (Couch 2015). Functional studies by Mesman et al. (2018) demonstrated this variant to have 81% homology directed repair capacity and 90% Cisplatin sensitivity compared to wild-type in BRCA2-deficient mouse embryonic stem cells, similar to non-pathogenic variants. BRCA2 Ser3291Cys was observed at an allele frequency of 0.08% (21/25790) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is located in the RAD51 binding domain and Phosphoserine residue by SDK1/2 (Roy 2012). 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 Ser3291Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122939 SCV000166197 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 3291 of the BRCA2 protein (p.Ser3291Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs200210279, ExAC 0.03%). This variant has been reported in individuals affected with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 135821). Experimental studies have shown that phosphorylation of the serine amino acid residue (S3291) may be important for BRCA2-RAD51 interaction (PMID: 15800615, 22194698). Furthermore, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this p.Ser3291Cys variant is likely to be disruptive. However, these predictions regarding the impact of this specific amino acid change have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.