Submissions for variant NM_032043.3(BRIP1):c.362C>G (p.Thr121Ser)

gnomAD frequency: 0.00002  dbSNP: rs777630298

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216740	SCV000276507	likely benign	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000216740	SCV000689386	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 121 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 BRIP1-related disorders in the literature. This variant has been identified in 4/251408 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705215	SCV000834201	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 121 of the BRIP1 protein (p.Thr121Ser). This variant is present in population databases (rs777630298, gnomAD 0.01%). 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: 232380). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800562	SCV002046215	uncertain significance	not provided	2022-12-23	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00012 (4/34592 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000216740	SCV002533701	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	curation