ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3236T>C (p.Ile1079Thr) (rs150813402)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218787 SCV000273236 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000218787 SCV000906472 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Counsyl RCV000663136 SCV000786280 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2018-04-02 criteria provided, single submitter clinical testing
GeneDx RCV000116154 SCV000150063 uncertain significance not provided 2017-04-03 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3236T>C at the cDNA level, p.Ile1079Thr (I1079T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Ile1079Thr was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Ile1079Thr occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Ile1079Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780057 SCV000917078 uncertain significance not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.3236T>C (p.Ile1079Thr) results in a non-conservative amino acid change located outside of any known functional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This frequency is lower than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (7.8e-06 vs 6.3e-05), allowing no conclusion about variant significance. The c.3236T>C has been reported in the literature in individuals affected with Breast Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000204707 SCV000261454 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1079 of the BRIP1 protein (p.Ile1079Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs150813402, ExAC 0.01%) but has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 128185). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000116154 SCV000888000 uncertain significance not provided 2018-07-09 criteria provided, single submitter clinical testing

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