ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2515T>C (p.Tyr839His) (rs587778125)

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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 RCV000220257 SCV000277358 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-23 criteria provided, single submitter clinical testing
ITMI RCV000120344 SCV000084496 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000120344 SCV000918816 uncertain significance not specified 2018-02-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2515T>C (p.Tyr839His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 120622 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.2515T>C variant has not been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer to our knowledge, and no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000686331 SCV000813845 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 839 of the BRCA2 protein (p.Tyr839His). The tyrosine residue is weakly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 133735). 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 histidine 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 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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