Submissions for variant NM_032043.3(BRIP1):c.3367A>G (p.Thr1123Ala)

dbSNP: rs754056526

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679784	SCV000565859	uncertain significance	not provided	2015-03-04	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.3367A>G at the cDNA level, p.Thr1123Ala (T1123A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Thr1123Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Thr1123Ala occurs at a position that is conserved across mammals, with Alanine being the naturally occurring amino acid at this position in two species, and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRIP1 Thr1123Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478257	SCV000600915	uncertain significance	not specified	2017-03-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679784	SCV000807143	uncertain significance	not provided	2016-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811671	SCV000951949	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1123 of the BRIP1 protein (p.Thr1123Ala). This variant is present in population databases (rs754056526, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 418644). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV001020106	SCV001181539	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	The p.T1123A variant (also known as c.3367A>G), located in coding exon 19 of the BRIP1 gene, results from an A to G substitution at nucleotide position 3367. The threonine at codon 1123 is replaced by alanine, an amino acid with similar properties. This amino acid position is 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.
Sema4, Sema4	RCV001020106	SCV002533688	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	curation
Baylor Genetics	RCV003463980	SCV004214613	uncertain significance	Familial cancer of breast	2023-10-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001020106	SCV004362871	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1123 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250768 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.