ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6931C>A (p.Pro2311Thr) (rs730881551)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160123 SCV000210407 uncertain significance not provided 2016-10-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6931C>A at the cDNA level, p.Pro2311Thr (P2311T) at the protein level, and results in the change of a Proline to a Threonine (CCA>ACA). Using alternate nomenclature, this variant would be defined as BRCA2 7159C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro2311Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Pro2311Thr occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Pro2311Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000557928 SCV000635545 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-05-02 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 2311 of the BRCA2 protein (p.Pro2311Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182235). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000564056 SCV000661303 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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