ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6119T>C (p.Ile2040Thr) (rs876659473)

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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 RCV000216340 SCV000275989 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589937 SCV000694938 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6119T>C (p.Ile2040Thr) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome, and Ile2040 is not located in a known functional domain of the Breast cancer type 2 susceptibility protein. This variant was absent in 120840 control chromosomes and has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. One clinical lab classified the variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000467262 SCV000549680 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2040 of the BRCA2 protein (p.Ile2040Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. 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: 231981). 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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