ClinVar Genomic variation as it relates to human health
NM_032043.3(BRIP1):c.3103C>T (p.Arg1035Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(8); Benign(4); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_032043.3(BRIP1):c.3103C>T (p.Arg1035Cys)
Variation ID: 140819 Accession: VCV000140819.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.2 17: 61683943 (GRCh38) [ NCBI UCSC ] 17: 59761304 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 6, 2017 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032043.3:c.3103C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_114432.2:p.Arg1035Cys missense NC_000017.11:g.61683943G>A NC_000017.10:g.59761304G>A NG_007409.2:g.184617C>T LRG_300:g.184617C>T LRG_300t1:c.3103C>T LRG_300p1:p.Arg1035Cys - Protein change
- R1035C
- Other names
- -
- Canonical SPDI
- NC_000017.11:61683942:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00047
Exome Aggregation Consortium (ExAC) 0.00058
The Genome Aggregation Database (gnomAD), exomes 0.00059
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BRIP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5541 | 5595 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Sep 29, 2022 | RCV000129008.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 21, 2016 | RCV000412441.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 15, 2018 | RCV000410906.9 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Apr 1, 2024 | RCV000590794.24 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV001081667.10 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001355322.4 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 6, 2024 | RCV001800423.14 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 25, 2023 | RCV003149886.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV003315867.5 | |
Benign (1) |
criteria provided, single submitter
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Jul 9, 2019 | RCV004532542.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Benign
(May 27, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699713.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Oct 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group J
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000490057.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Oct 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm of ovary
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000490058.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Jan 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279384.11
First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Uncertain significance
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551152.5
First in ClinVar: Jul 27, 2022 Last updated: Feb 14, 2024 |
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Benign
(Sep 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000172905.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Sep 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885118.1
First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019 |
Comment:
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 … (more)
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. (less)
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Likely benign
(Jul 17, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000910605.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Jan 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group J
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001284863.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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 … (more)
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. (less)
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Benign
(Oct 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046314.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Uncertain significance
(Dec 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002068138.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
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 … (more)
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. (less)
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Likely benign
(Sep 16, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002533677.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019402.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
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.
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048178.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
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) … (more)
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. (less)
Clinical Features:
Neoplasm (present) , Leukemia (present)
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Likely benign
(Apr 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838374.2
First in ClinVar: Mar 11, 2023 Last updated: Feb 04, 2024 |
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Likely benign
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Fanconi anemia complementation group J
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000253627.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
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Benign
(Jul 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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BRIP1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004732054.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
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).
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Likely benign
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004009820.7
First in ClinVar: Jul 16, 2023 Last updated: May 12, 2024 |
Comment:
BRIP1: BP4, BS2
Number of individuals with the variant: 2
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550180.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. | Pritchard AL | PloS one | 2018 | PMID: 29641532 |
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. | Shindo K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28767289 |
No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. | Easton DF | Journal of medical genetics | 2016 | PMID: 26921362 |
RBP-Var: a database of functional variants involved in regulation mediated by RNA-binding proteins. | Mao F | Nucleic acids research | 2016 | PMID: 26635394 |
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
Reconfiguring phosphorylation signaling by genetic polymorphisms affects cancer susceptibility. | Wang Y | Journal of molecular cell biology | 2015 | PMID: 25722345 |
Mutations in Fanconi anemia genes and the risk of esophageal cancer. | Akbari MR | Human genetics | 2011 | PMID: 21279724 |
Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. | Seal S | Nature genetics | 2006 | PMID: 17033622 |
Text-mined citations for rs45437094 ...
HelpRecord last updated Jun 02, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.