ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1478C>T (p.Pro493Leu) (rs786202916)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165981 SCV000216739 likely benign Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000165981 SCV000903160 likely benign Hereditary cancer-predisposing syndrome 2016-10-11 criteria provided, single submitter clinical testing
Counsyl RCV000239257 SCV000488285 uncertain significance Breast-ovarian cancer, familial 2 2016-02-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000486205 SCV000591747 likely benign not specified 2012-11-15 criteria provided, single submitter clinical testing
GeneDx RCV000587856 SCV000566694 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1478C>T at the cDNA level, p.Pro493Leu (P493L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). Using alternate nomenclature, this variant would be defined as BRCA2 1706C>T. This variant was observed in at least two individuals with breast cancer (Yang 2017). BRCA2 Pro493Leu was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Pro493Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587856 SCV000694542 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1478C>T (p.Pro493Leu) variant involves the alteration of a non-conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome. although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowlege, reported in affected individuals via publications. Although, multiple clinical diagnostic laboratories/databases have cited the variant with a classification of "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000534241 SCV000635162 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-14 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 493 of the BRCA2 protein (p.Pro493Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs786202916, ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 28664506), and an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 186393). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486205 SCV000296751 uncertain significance not specified 2016-12-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587856 SCV000888981 uncertain significance not provided 2018-01-17 criteria provided, single submitter clinical testing

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