ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.143C>A (p.Thr48Lys) (rs755317452)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000584278 SCV000689261 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000216242 SCV000279641 uncertain significance not provided 2015-11-23 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.143C>A at the cDNA level, p.Thr48Lys (T48K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant was observed in 1/3431 controls and 0/3236 cases in an ovarian cancer case-control study (Ramus 2015). BRIP1 Thr48Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRIP1 Thr48Lys occurs at a position that is conserved across species and is located in the Helicase ATP-binding domain (Cantor 2011, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Thr48Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000698138 SCV000826781 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 48 of the BRIP1 protein (p.Thr48Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is present in population databases (rs755317452, ExAC 0.02%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 234642). 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 disruptive, 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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