ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4090A>G (p.Ile1364Val) (rs56248502)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130224 SCV000185064 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000410854 SCV000489410 uncertain significance Breast-ovarian cancer, familial 2 2016-10-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587668 SCV000694742 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4090A>G (p.Ile1364Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120860 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000557623 SCV000635334 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1364 of the BRCA2 protein (p.Ile1364Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. 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: 141629). 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 valine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587668 SCV000889042 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing

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