ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2723C>T (p.Thr908Ile) (rs786201919)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164448 SCV000215090 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000586440 SCV000329160 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2723C>T at the cDNA level, p.Thr908Ile (T908I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant was observed in an individual with invasive breast cancer (Easton 2016). BRIP1 Thr908Ile was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Thr908Ile occurs at a position that is not conserved and is located in the BRCA1 binding domain (Cantor 2011). 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 Thr908Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586440 SCV000699702 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The c.2723C>T (p.Thr908I) in BRIP1 gene is a missense change that involves a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain. The variant is absent from the control population dataset of ExAC and has not, to our knowledge, been reported in affected individuals via published. One by reputable database/clinical laboratory classified the variant as VUS. Taking together, the variant was classified as VUS.
Invitae RCV000699974 SCV000828707 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 908 of the BRIP1 protein (p.Thr908Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 185088). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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