ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7030A>G (p.Ile2344Val) (rs876658231)

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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 RCV000218525 SCV000273190 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587486 SCV000695017 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7030A>G (p.Ile2344Val) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting 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. A reputable clinical laboratory cites the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000461227 SCV000549732 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-06-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2344 of the BRCA2 protein (p.Ile2344Val). 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. 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 also 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 mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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