ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2444T>C (p.Met815Thr) (rs1303254121)

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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 RCV000509649 SCV000607840 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000509649 SCV000683484 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589134 SCV000694597 uncertain significance not provided 2016-02-08 criteria provided, single submitter clinical testing Variant summary: This c.2444T>C variant affects a non-conserved nucleotide, resulting in amino acid change from Met to Thr. 3/5 in-silico tools predict this variant to be benign. This variant was not found in approximately 120364 control chromosomes from broad and large populations of ExAC. The variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical 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 was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000637404 SCV000758860 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 815 of the BRCA2 protein (p.Met815Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine 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: 441305). 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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