ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1897A>C (p.Ile633Leu) (rs765314472)

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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 RCV000164796 SCV000215476 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164796 SCV000292193 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
GeneDx RCV000217145 SCV000279945 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1897A>C at the cDNA level, p.Ile633Leu (I633L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATC>CTC). This variant has not, to our knowledge, been published in the literature as a pathogenic germline variant. However, it has been reported as a somatic variant in a gastric cell line (Liu 2014) BRIP1 Ile633Leu 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 Leucine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Ile633Leu occurs at a position that is conserved 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 Ile633Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000457977 SCV000547297 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2017-04-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 633 of the BRIP1 protein (p.Ile633Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs765314472, ExAC 0.02%) but has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 185386). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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