ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.370A>G (p.Thr124Ala) (rs45617634)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212299 SCV000210870 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.370A>G at the cDNA level, p.Thr124Ala (T124A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant was observed in an individual with a personal history of a Lynch syndrome associated cancer and/or polyps (Yurgelun 2015). BRIP1 Thr124Ala was not observed at significant allele frequency 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 Thr124Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160363 SCV000215430 likely benign Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000205266 SCV000261745 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 124 of the BRIP1 protein (p.Thr124Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs45617634, ExAC 0.009%). This variant has been reported in an individual undergoing Lynch syndrome testing (PMID: 25980754) and in an unaffected control (PMID: 17033622). ClinVar contains an entry for this variant (Variation ID: 182371). 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 alanine 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.
Counsyl RCV000409265 SCV000490001 uncertain significance Fanconi anemia, complementation group J 2016-09-16 criteria provided, single submitter clinical testing
Counsyl RCV000410368 SCV000490002 uncertain significance Neoplasm of ovary 2016-09-16 criteria provided, single submitter clinical testing
Color RCV000160363 SCV000689388 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-17 criteria provided, single submitter clinical testing

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