ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122939 SCV000166197 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-27 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 observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 135821). This variant has been reported not to substantially affect BRCA2 protein function (PMID: 29988080). 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.
Ambry Genetics RCV000129292 SCV000184053 likely benign Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
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.
Color Health, Inc RCV000129292 SCV000684096 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-17 criteria provided, single submitter clinical testing

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