ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1655T>C (p.Ile552Thr) (rs369340666)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132461 SCV000187555 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000204568 SCV000261268 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 552 of the BRIP1 protein (p.Ile552Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs369340666, ExAC 0.01%). This variant has been reported in the literature in individuals with a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754), colorectal cancer (PMID: 28135145), ovarian cancer (PMID: 26315354), and breast cancer (PMID: 26921362), as well as in an unaffected individual (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 142965). 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 disruptive, 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.
GeneDx RCV000215881 SCV000278898 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1655T>C at the cDNA level, p.Ile552Thr (I552T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has been observed in an individual with serous ovarian cancer, an individual with a Lynch syndrome-associated cancer and/or polyps, an individual with breast cancer, and in a healthy control (Ramus 2015, Yurgelun 2015, Easton 2016). BRIP1 Ile552Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Ile552Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132461 SCV000684149 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-07 criteria provided, single submitter clinical testing
Counsyl RCV000662589 SCV000785216 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-06-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000215881 SCV000887983 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing

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