ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1952T>C (p.Ile651Thr) (rs757305097)

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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 RCV000222634 SCV000273217 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-24 criteria provided, single submitter clinical testing The p.I651T variant (also known as c.1952T>C), located in coding exon 13 of the BRIP1 gene, results from a T to C substitution at nucleotide position 1952. The isoleucine at codon 651 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000218247 SCV000278899 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1952T>C at the cDNA level, p.Ile651Thr (I651T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant was reported in an unaffected control individual but absent from breast and ovarian cancer cases (Weber-Lassalle 2018). BRIP1 Ile651Thr was not observed at a 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Ile651Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230038 SCV000290998 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-08-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 651 of the BRIP1 protein (p.Ile651Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs757305097, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 229862). 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.
Color RCV000222634 SCV000689298 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-29 criteria provided, single submitter clinical testing

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