Submissions for variant NM_032043.3(BRIP1):c.3475G>A (p.Ala1159Thr)

dbSNP: rs368610199

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222116	SCV000274370	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.
GeneDx	RCV000521348	SCV000618487	uncertain significance	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000222116	SCV000903943	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1159 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 1/250088 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	RCV000808973	SCV000949107	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1159 of the BRIP1 protein (p.Ala1159Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 230724). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000521348	SCV002010905	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing