rs373040333

Description

The p.T1050N variant (also known as c.3149C>A), located in coding exon 19 of the BRIP1 gene, results from a C to A substitution at nucleotide position 3149. The threonine at codon 1050 is replaced by asparagine, an amino acid with similar properties. This alteration was reported in 2/190 Iranian Turkmen with esophageal squamous cell carcinoma (ESCC) (Akbari MR et al. Hum. Genet. 2011 May;129:573-82). This variant was also reported in a male diagnosed with MMR-proficient rectal cancer at 47 years (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). 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.

This variant is denoted BRIP1 c.3149C>A at the cDNA level, p.Thr1050Asn (T1050N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). This variant has been reported in at least one individual with colon cancer and another with early onset breast cancer (Tung 2015, Pearlman 2017, Yurgelun 2017). BRIP1 Thr1050Asn was observed at an allele frequency of 0.08% (24/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the BRCA1 binding domain (Cantor 2011). 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 Thr1050Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.