ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9718G>A (p.Val3240Ile) (rs80359240)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165570 SCV000216304 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000114156 SCV000147702 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000165570 SCV000906965 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000587392 SCV000564806 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9718G>A at the cDNA level, p.Val3240Ile (V3240I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 9946G>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Val3240Ile was observed at an allele frequency of 0.01% (2/15,014) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Val3240Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587392 SCV000695263 uncertain significance not provided 2016-04-04 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 4/4 in silico programs (SNPs&Go not captured here 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 knowledge, reported in affected individuals via publications. Multiple reputable clinical laboratories/databases cite the variant with a classification of "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000045890 SCV000073903 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 3240 of the BRCA2 protein (p.Val3240Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000479353 SCV000600874 uncertain significance not specified 2016-12-14 criteria provided, single submitter clinical testing

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