ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1444A>G (p.Ile482Val) (rs142744352)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589605 SCV000150037 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1444A>G at the cDNA level, p.Ile482Val (I482V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has been identified in a cohort of 1,250 individuals with personal history of Lynch syndrome-associated cancer and/or polyps undergoing genetic testing for Lynch syndrome using a multi-gene panel (Yurgelun 2015), and was identified in 0/1,853 cases and 1/2,001 controls in a breast cancer case-control study (Easton 2016). BRIP1 Ile482Val was observed at an allele frequency of 0.01% (2/18,608) in individuals of East Asian ancestry 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Ile482Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000195858 SCV000255147 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 valine at codon 482 of the BRIP1 protein (p.Ile482Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs142744352, ExAC 0.007%). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 128160). 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 has uncertain impact on BRIP1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000218129 SCV000278488 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000218129 SCV000537518 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589605 SCV000699664 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.1444A>G (p.Ile482Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 3/88242 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000658 (3/45614). This frequency is greater than the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant was cited in 1 patient with a history of Lynch syndrome-associated cancer and/or polyps; however, co-segregation studies were not done, and thus it cannot be concluded that this variant was causative in this patient. Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000662396 SCV000784811 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-01-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589605 SCV001134004 uncertain significance not provided 2019-07-09 criteria provided, single submitter clinical testing

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