Submissions for variant NM_032043.3(BRIP1):c.854A>G (p.His285Arg)

gnomAD frequency: 0.00017  dbSNP: rs141055990

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131157	SCV000186099	likely benign	Hereditary cancer-predisposing syndrome	2020-11-05	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	RCV000220964	SCV000279545	uncertain significance	not provided	2023-12-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31871109, 26822149, 25980754, 32959997, 33471991, 35264596)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231925	SCV000291059	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 285 of the BRIP1 protein (p.His285Arg). This variant is present in population databases (rs141055990, gnomAD 0.08%). This missense change has been observed in individual(s) with breast cancer (PMID: 26822149, 31871109, 32959997). ClinVar contains an entry for this variant (Variation ID: 142179). 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 expected to disrupt BRIP1 protein function with a positive 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	RCV000411077	SCV000490037	uncertain significance	Fanconi anemia complementation group J	2016-10-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000412159	SCV000490038	uncertain significance	Ovarian neoplasm	2016-10-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000411077	SCV000839391	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000220964	SCV000861413	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000220964	SCV000889228	uncertain significance	not provided	2022-10-29	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00076 (19/24968 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 31871109 (2019), 32959997 (2020), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRIP1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000131157	SCV000903607	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 285 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 32959997). This variant has been identified in 19/282340 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781177	SCV000919056	likely benign	not specified	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.854A>G (p.His285Arg) results in a non-conservative amino acid change located in the ATP-binding domain (IPR014001) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250946 control chromosomes, predominantly at a frequency of 0.00092 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.854A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Uyisenga_2020, Adedokun_2020), however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000781177	SCV002067595	uncertain significance	not specified	2018-12-21	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225442	SCV002505043	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131157	SCV002529241	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315902	SCV004019427	uncertain significance	Familial cancer of breast	2023-03-01	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003315902	SCV004031083	uncertain significance	Familial cancer of breast	2023-08-30	criteria provided, single submitter	clinical testing	The BRIP1 c.854A>G (p.His285Arg) missense change has a maximum subpopulation frequency of 0.076% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 32885271, 32959997). This variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV003315902	SCV004214642	uncertain significance	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356435	SCV001551601	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.His285Arg variant was not identified in the literature. The variant was identified in dbSNP (ID: rs141055990) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and four other submitters). The variant was identified in control databases in 19 of 276644 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 19 of 24032 chromosomes (freq: 0.0008), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His285 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004732697	SCV005349202	uncertain significance	BRIP1-related disorder	2024-08-14	no assertion criteria provided	clinical testing	The BRIP1 c.854A>G variant is predicted to result in the amino acid substitution p.His285Arg. This variant was reported in multiple individuals with breast cancer (Table 5, Adedokun et al. 2020. PubMed ID: 31871109; Table 3, Uyisenga et al. 2020. PubMed ID: 32959997; Guindalini RSC et al. 2022. PubMed ID: 35264596). However, no additional studies were performed to help assess the pathogenicity of this variant. This variant is reported in 0.076% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142179/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.