rs45437094
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_032043.3(BRIP1):c.3103C>T(p.Arg1035Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,614,128 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1035H) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.3103C>T | p.Arg1035Cys | missense_variant | 20/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.3103C>T | p.Arg1035Cys | missense_variant | 20/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152146Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000589 AC: 148AN: 251444Hom.: 0 AF XY: 0.000773 AC XY: 105AN XY: 135888
GnomAD4 exome AF: 0.000319 AC: 467AN: 1461864Hom.: 2 Cov.: 34 AF XY: 0.000443 AC XY: 322AN XY: 727234
GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152264Hom.: 1 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74460
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | BRIP1: BP4, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 06, 2017 | The p.Arg1035Cys variant (rs45437094) has been reported in the medical literature in at least one case of non-serous ovarian cancer (Ramus 2015). The p.Arg1035Cys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.48% in the South Asian population (identified in 135 out of 30,782 chromosomes; 0 homozygotes), and is listed in ClinVar (likely benign/uncertain significance; Variant ID: 140819). The arginine at codon 1,035 is weakly conserved considering 12 species (Alamut software v2.9.0), and computational analyses suggest that this variant does not affect the Brip1 protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). While the p.Arg1035Cys appears to be a benign polymorphism in the South Asian population, the available information is insufficient to determine the clinical significance with certainty. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 27, 2016 | Variant summary: The BRIP1 c.3103C>T (p.Arg1035Cys) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome. This variant was found in 72/125562 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0039976 (66/16510). This frequency is about 64 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), highly suggesting this is a benign polymorphism found primarily in the populations of South Asian origin. Additionally, the variant of interest was found to co-occur with a likely pathogenic PALB2 variant, c.829_832delGACC, in one internal LCA specimen. Furthermore, one clinical diagnostic laboratory recently classified this variant as likely benign. Taken together, this variant is classified as Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 26921362, 25722345, 21279724, 17033622) - |
not specified Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 03, 2020 | DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.3103C>T, in exon 20 that results in an amino acid change, p.Arg1035Cys. This sequence change does not appear to have been previously described in patients with BRIP1-related disorders and has been described in the gnomAD database with a frequency of 0.44% in the South Asian sub-population (dbSNP rs45437094). The p.Arg1035Cys change affects a poorly conserved amino acid residue located in a domain of the BRIP1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1035Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1035Cys change remains unknown at this time. - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 17, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 16, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 29, 2022 | This alteration is classified as 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. - |
Fanconi anemia complementation group J Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 15, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 21, 2016 | - - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 01, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.R1035C in BRIP1 (NM_032043.3) has been reported previously in 2/189 Turkmen patients with esophageal squamous cell carcinoma (Akbari MR et al, 2011) and in a Caucasian patient diagnosed with a pancreatic neuroendocrine tumor (Shindo K et al, 2017). Variants in gene BRIP1 have been observed in individuals affected with Ovarian Cancer (Moyer et al, 2020 ). There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico tools predict the variant to be tolerated. For these reasons, this variant has been classified as Uncertain Significance. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRIP1 p.Arg1035Cys variant was identified in 1 of 26426 proband chromosomes (frequency: 3.78 E-05) from individuals or families with breast cancer and was not identified in 10484 control chromosomes from healthy individuals (Easton 2016). The variant was also identified in the following databases: dbSNP (ID: rs45437094) as With Uncertain significance allele, ClinVar with conflicting interpretations of pathogenicity (as likely benign by Invitae, and as uncertain significance by Ambry Genetics, Gene Dx and Counsyl), Clinvitae (5x), and Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 149 of 277168 chromosomes at a frequency of 0.000538 in the following populations: South Asian in 135 of 30782 chromosomes (freq. 0.004), Other in 149 of 6466 chromosomes (freq. 0.00016), European (Non-Finnish) in 11 of 126676 chromosomes (freq. 0.000087), East Asian in 1 of 18858 chromosomes (freq. 0.00005), and Latino in 1 of 34418 chromosomes (freq. 0.000029) (Genome Aggregation Consortium Feb 27, 2017). The p.Arg1035Cys residue is not 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, HumanSpliceFinder) 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. - |
Ovarian neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 21, 2016 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 25, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
BRIP1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 09, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at