ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1650T>G (p.Ile550Met) (rs587782254)

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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 RCV000130967 SCV000185882 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130967 SCV000684147 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing
GeneDx RCV000479209 SCV000568899 uncertain significance not provided 2016-11-23 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1650T>G at the cDNA level, p.Ile550Met (I550M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATT>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Ile550Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Ile550Met occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the helicase domain (Cantor 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Ile550Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000636069 SCV000757501 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 550 of the BRIP1 protein (p.Ile550Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 142127). 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: "Deleterious"; PolyPhen-2: "Possibly 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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