Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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. |
Invitae | RCV000204707 | SCV000261454 | uncertain significance | Familial cancer of breast; Fanconi anemia, complementation group J | 2019-12-17 | 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%). This variant has been observed in an individual affected with breast cancer (PMID: 26921362). 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 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 and their clinical significance is uncertain. 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. |
Ambry Genetics | RCV000218787 | SCV000273236 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-03-29 | criteria provided, single submitter | clinical testing | Insufficient or conflicting evidence |
Counsyl | RCV000663136 | SCV000786280 | uncertain significance | Fanconi anemia, complementation group J; Neoplasm of ovary | 2018-04-02 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000116154 | SCV000888000 | uncertain significance | not provided | 2018-07-09 | criteria provided, single submitter | clinical testing | |
Color | RCV000218787 | SCV000906472 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-09-10 | criteria provided, single submitter | clinical testing | |
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. |