ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9206G>T (p.Cys3069Phe) (rs587782091)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130600 SCV000185474 uncertain significance Hereditary cancer-predisposing syndrome 2015-02-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000215969 SCV000279521 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9206G>T at the cDNA level, p.Cys3069Phe (C3069F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGT>TTT). Using alternate nomenclature, this variant has been previously published as BRCA2 9434G>T. This variant was observed in at least one individual with a personal and family history of breast cancer (Meindl 2002) as well as a male with mismatch repair-proficient cecal cancer who also harbored a pathogenic SMAD4 variant (Pearlman 2017). BRCA2 Cys3069Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). 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 Cys3069Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000205419 SCV000261116 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-03-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 3069 of the BRCA2 protein (p.Cys3069Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs587782091, ExAC 0.002%). This variant has been reported in an individual affected with breast cancer (PMID: 11802209). This variant is also known as 9434G>T in the literature. ClinVar has an entry for this variant (Variation ID: 141897). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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