Submissions for variant NM_032043.3(BRIP1):c.3571A>G (p.Ile1191Val)

gnomAD frequency: 0.00003  dbSNP: rs761405340

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166662	SCV000217467	likely benign	Hereditary cancer-predisposing syndrome	2024-02-14	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	RCV000198324	SCV000255174	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1191 of the BRIP1 protein (p.Ile1191Val). This variant is present in population databases (rs761405340, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362, 28202063, 28767289). ClinVar contains an entry for this variant (Variation ID: 186989). 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.
GeneDx	RCV000219026	SCV000279885	uncertain significance	not provided	2024-08-11	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast, pancreatic, and other cancers (PMID: 26921362, 28202063, 28767289, 29360161, 32659497); This variant is associated with the following publications: (PMID: 26921362, 28202063, 28767289, 29360161, 32659497, 33471991, 28492532, 36243179)
Counsyl	RCV000662435	SCV000784894	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166662	SCV000902870	likely benign	Hereditary cancer-predisposing syndrome	2016-06-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781167	SCV000919046	uncertain significance	not specified	2017-11-20	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 variant, c.3571A>G (p.ile1191Val) involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is located outside of any know functional domain or repeat (InterPro). No functional studies confirming an effect of this change on protein function have been published at the time of evaluation. The variant is present in the control population dataset gnomAD at a frequency of 0.00003 (8/245616 chrs tested), which does not exceed the maximal expected allele frequency for a pathogenic BRIP1 variant (0.00006). The variant has been reported in at least two BrC individuals without strong evidence for causality (Easton_2016; Jalkh_2017). The variant is cited as uncertain significance by reputable databases/clinical laboratories. Taken together, the variant was classified as a "Variant of Uncertain Significance (VUS)," until new information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219026	SCV001470271	uncertain significance	not provided	2020-01-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798598	SCV002043635	uncertain significance	Breast and/or ovarian cancer	2019-09-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166662	SCV002533699	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003316056	SCV004019375	uncertain significance	Familial cancer of breast	2023-02-28	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316056	SCV004239121	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1191 of the BRIP1 protein (p.Ile1191Val). . This amino acid position is poorly conserved. This variant is present in population databases (rs761405340, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362, 28202063, 28767289). ClinVar contains an entry for this variant (Variation ID: 186989).In silico analysis supports that this missense variant does not alter protein structure/function. 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.