ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10238C>A (p.Thr3413Lys) (rs730881584)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509846 SCV000608256 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000509846 SCV000906629 likely benign Hereditary cancer-predisposing syndrome 2016-06-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586406 SCV000694501 uncertain significance not provided 2017-04-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.10238C>A (p.Thr3413Lys) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. This variant is absent in 118766 control chromosomes (ExAC). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. A reputable database cites the variant with a classification of "UV." 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 RCV000698928 SCV000827619 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 3413 of the BRCA2 protein (p.Thr3413Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. 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. ClinVar contains an entry for this variant (Variation ID: 441516). 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.

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