rs786202630
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_032043.3(BRIP1):c.2594G>A(p.Arg865Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R865W) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2594G>A | p.Arg865Gln | missense_variant | 19/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2594G>A | p.Arg865Gln | missense_variant | 19/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250442Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135716
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461760Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13AN XY: 727186
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74398
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2023 | The p.R865Q variant (also known as c.2594G>A), located in coding exon 18 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2594. The arginine at codon 865 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was identified in 0/1313 cases of breast cancer and 1/1123 controls (Easton DF et al. J Med Genet, 2016 05;53:298-309). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 08, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 15, 2023 | This missense variant replaces arginine with glutamine at codon 865 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 not been reported in individuals affected with hereditary cancer in the literature. In a breast cancer case-control study, this variant was absent in 1313 breast cancer cases and observed in 1/1123 controls (PMID: 26921362). This variant has been identified in 2/250442 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 30, 2023 | Variant summary: BRIP1 c.2594G>A (p.Arg865Gln) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) 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 1.2e-05 in 252688 control chromosomes (gnomAD and Easton_2016). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2594G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer and Adult acute lymphoblastic leukemia (examples, Bhai_2021, Douglas_2022), without strong evidence for causality. Co-occurrences with other pathogenic variant(s) have been reported (RET c.2410G>A, p.Val804Met) in an adult patient with cute lymphoblastic leukemia (Bhai_2021), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 35739278, 26921362). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 01, 2016 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Absent from breast cancer cases but observed in cancer-free controls in case-control study (Easton 2016); This variant is associated with the following publications: (PMID: 26921362) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 29, 2021 | - - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | May 29, 2023 | variant of uncertain significance was detected in the BRIP1 gene (c.2594G>A). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 865 of the BRIP1 protein (p.Arg865Gln). This variant is present in population databases (rs781609846, gnomAD 0.01%). This amino acid position is moderate conserved ( PhyloP= 5.58 . 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: 186015). t In silico analysis supports that this missense variant has a deleterious effect on 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. BRIP1 gene cause susceptibility to breast cancer (OMIM 114480). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 25, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 865 of the BRIP1 protein (p.Arg865Gln). This variant is present in population databases (rs781609846, gnomAD 0.01%). This missense change has been observed in individual(s) with BRIP1-related conditions (PMID: 34326862, 35739278). ClinVar contains an entry for this variant (Variation ID: 186015). 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. - |
BRIP1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 05, 2019 | The BRIP1 c.2594G>A (p.Arg865Gln) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is found at a frequency of 0.000205 in the African population of the Genome Aggregation Database but this is based on two alleles only in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, the p.Arg865Gln variant is classified as a variant of uncertain significance for BRIP1-related disorders. - |
Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 10, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at