ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2750T>C (p.Ile917Thr) (rs587781492)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129456 SCV000184226 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000697286 SCV000825886 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-03-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 917 of the BRCA1 protein (p.Ile917Thr). The isoleucine residue is moderately 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 BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 141097). 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 threonine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759509 SCV000888870 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175509 SCV001339114 uncertain significance not specified 2020-03-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2750T>C (p.Ile917Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250846 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2750T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000129456 SCV001359694 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-18 criteria provided, single submitter clinical testing

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