ClinVar Miner

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

gnomAD frequency: 0.00017  dbSNP: rs141055990
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131157 SCV000186099 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing The p.H285R variant (also known as c.854A>G), located in coding exon 6 of the BRIP1 gene, results from an A to G substitution at nucleotide position 854. The histidine at codon 285 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000220964 SCV000279545 uncertain significance not provided 2022-01-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with breast cancer (Uyisenga 2020); This variant is associated with the following publications: (PMID: 31871109, 26822149, 25980754, 32959997)
Invitae RCV000231925 SCV000291059 uncertain significance Familial cancer of breast; Fanconi anemia complementation group J 2021-12-17 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: 31871109, 32959997). ClinVar contains an entry for this variant (Variation ID: 142179). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 Neoplasm of ovary 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 2020-07-16 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131157 SCV000903607 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-10 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
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.

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