Submissions for variant NM_032043.3(BRIP1):c.2706A>G (p.Ile902Met)

gnomAD frequency: 0.00001  dbSNP: rs587780244

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656814	SCV000150057	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing	Observed in an individual with breast cancer (Tung et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28873162, 11301010, 25186627)
Ambry Genetics	RCV000116148	SCV000184658	likely benign	Hereditary cancer-predisposing syndrome	2024-11-26	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	RCV000229209	SCV000291021	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 902 of the BRIP1 protein (p.Ile902Met). This variant is present in population databases (rs587780244, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 128179). 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.
Counsyl	RCV000410789	SCV000489951	uncertain significance	Fanconi anemia complementation group J	2016-08-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000412341	SCV000489952	uncertain significance	Ovarian neoplasm	2016-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212329	SCV000600906	uncertain significance	not specified	2017-07-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116148	SCV000903015	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 902 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 reported in an individual affected with early-onset breast cancer, an individual affected with colorectal cancer, and an individual affected with an unspecified advanced cancer (PMID: 25186627, 28873162; DOI: 10.1200/JCO.2020.38.15_suppl.1538). This variant has been identified in 5/251356 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.
Sema4, Sema4	RCV000116148	SCV002533643	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315654	SCV004019472	uncertain significance	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.