ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.728T>C (p.Ile243Thr) (rs587781860)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130174 SCV000185011 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence,Rarity in general population databases (dbSNP, ESP, 1000 Genomes)
Invitae RCV000473070 SCV000547305 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 243 of the BRIP1 protein (p.Ile243Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs587781860, ExAC 0.007%). This variant has been reported in individuals affected with breast cancer and colorectal cancer (PMID: 26976419, 28135145), and one healthy control individual (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 141590). 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.
GeneDx RCV000484934 SCV000569204 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.728T>C at the cDNA level, p.Ile243Thr (I243T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has been observed in one individual with colorectal cancer, one with a Lynch syndrome-associated tumor and/or colon polyps, and two with breast cancer, but has also been observed in a healthy control (Ramus 2015, Yurgelun 2015, Tung 2016, Yurgelun 2017). BRIP1 Ile243Thr was observed at an allele frequency of 0.007% (5/66718 alleles) in individuals of European ancestry 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 Ile243Thr occurs at a position that is not conserved and is not located in a functional domain. 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 Ile243Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics RCV000709557 SCV000839392 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484934 SCV000889224 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing
Color RCV000130174 SCV000911037 likely benign Hereditary cancer-predisposing syndrome 2016-10-06 criteria provided, single submitter clinical testing

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