Submissions for variant NM_032043.3(BRIP1):c.878A>G (p.Asn293Ser)

gnomAD frequency: 0.00001  dbSNP: rs746599076

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000319358	SCV000329153	uncertain significance	not provided	2021-05-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with uterine cancer (Lu 2015); This variant is associated with the following publications: (PMID: 26689913)
Ambry Genetics	RCV000573698	SCV000661491	likely benign	Hereditary cancer-predisposing syndrome	2023-11-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636175	SCV000757607	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 293 of the BRIP1 protein (p.Asn293Ser). This variant is present in population databases (rs746599076, gnomAD 0.006%). 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: 279708). 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	RCV000319358	SCV000889229	uncertain significance	not provided	2017-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000573698	SCV001355685	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 293 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 been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000627), and it also has been reported in an individual affected with uterine cancer (PMID: 26689913). This variant has been identified in 2/250894 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.