ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2705T>C (p.Ile902Thr) (rs1060501781)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465302 SCV000547384 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 902 of the BRIP1 protein (p.Ile902Thr). 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 been observed in an individual affected with pancreatic cancer (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 407876). 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.
Integrated Genetics/Laboratory Corporation of America RCV000589053 SCV000699701 uncertain significance not specified 2019-09-12 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2705T>C (p.Ile902Thr) 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 251352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2705T>C has been reported in the literature in individuals affected with breast cancer and pancreatic cancer (Shindo_2017, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other 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 RCV000773139 SCV000906645 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000773139 SCV001177170 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing Insufficient evidence

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