ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.797C>T (p.Thr266Met) (rs550031006)

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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 RCV000448094 SCV000661480 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000448094 SCV000537590 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
Counsyl RCV000662521 SCV000785075 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-04-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000198777 SCV000895114 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000116165 SCV000150074 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.797C>T at the cDNA level, p.Thr266Met (T266M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). BRIP1 Thr266Met was observed in a control subject in a breast cancer case-control study, but was not observed in any breast cancer cases (Easton 2016). This variant was observed at an allele frequency of 0.01% (1/10138 alleles) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). BRIP1 Thr266Met 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 Thr266Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000198777 SCV000255180 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 266 of the BRIP1 protein (p.Thr266Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs550031006, ExAC 0.02%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 128196). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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