ClinVar Genomic variation as it relates to human health
NM_032043.3(BRIP1):c.2684_2687del (p.Val894_Ser895insTer)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_032043.3(BRIP1):c.2684_2687del (p.Val894_Ser895insTer)
Variation ID: 241642 Accession: VCV000241642.38
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 17q23.2 17: 61686054-61686057 (GRCh38) [ NCBI UCSC ] 17: 59763415-59763418 (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 Apr 27, 2017 May 12, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032043.3:c.2684_2687del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_114432.2:p.Val894_Ser895insTer nonsense NM_032043.2:c.2684_2687delCCAT NC_000017.11:g.61686056_61686059del NC_000017.10:g.59763417_59763420del NG_007409.2:g.182503_182506del LRG_300:g.182503_182506del LRG_300t1:c.2684_2687del LRG_300p1:p.Val894_Ser895insTer - Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:61686053:ATGGAT:AT
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV000232131.13 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV000481257.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2022 | RCV000563726.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 19, 2022 | RCV002288925.3 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001358606.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 2, 2020 | RCV001310103.3 | |
not provided (1) |
no classification provided
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- | RCV001535435.3 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 11, 2019 | RCV001270931.3 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 4, 2021 | RCV001391201.3 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2023 | RCV002467445.7 |
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
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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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Pathogenic
(Jan 30, 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: SCV000291016.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser895*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ser895*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs760551339, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25330149). ClinVar contains an entry for this variant (Variation ID: 241642). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm of ovary
Affected status: yes
Allele origin:
germline
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Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499636.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(Mar 16, 2022)
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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: SCV000569475.5
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29368626, 25330149, 26921362, 29922827, 29961768, 31589614, 32885271) (less)
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Pathogenic
(Dec 13, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684229.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 4 nucleotides in exon 19 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant deletes 4 nucleotides in exon 19 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer, pancreatic cancer, gastrointestinal stromal tumor, or hyperplastic polyposis (PMID: 25330149, 29961768, 30680046, 31512090). This variant has been identified in 4/282712 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 09, 2021)
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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: SCV000668876.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.2684_2687delCCAT pathogenic mutation, located in coding exon 18 of the BRIP1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2684 to … (more)
The c.2684_2687delCCAT pathogenic mutation, located in coding exon 18 of the BRIP1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2684 to 2687, causing a translational frameshift with a predicted alternate stop codon (p.S895*). This mutation has been reported in multiple individuals with a personal and/or family history of breast cancer (Cybulski C et al. Clin Genet, 2015 Oct;88:366-70; Cybulski C et al. Int J Cancer, 2019 12;145:3311-3320; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Dorling et al. N Engl J Med. 2021 02;384:428-439), including an individual with male breast cancer (Scarpitta R et al. Breast Cancer Res Treat, 2019 Dec;178:557-564). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Mar 05, 2022)
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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: SCV002533641.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRIP1 c.2684_2687delCCAT (p.S895X) variant has been reported in at least 3 individuals with breast cancer, pancreatic cancer or gastrointestinal stromal tumor (PMID: 25330149, 29961768, … (more)
The BRIP1 c.2684_2687delCCAT (p.S895X) variant has been reported in at least 3 individuals with breast cancer, pancreatic cancer or gastrointestinal stromal tumor (PMID: 25330149, 29961768, 31589614, 32885271). The variant was also reported in a large breast cancer case control study in 2/60466 cases and 1/53461 controls (PMID: 33471991). This variant causes a frameshift that results in premature termination at position 895. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss of function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). The variant was observed in 1/24966 chromosomes of the African/African American subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 241642). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jul 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group J
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579034.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM2_SUP
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: research
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Familial cancer of breast
Affected status: no
Allele origin:
germline
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV002762806.2
First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023 |
Comment:
PVS1, PS4_STR
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Pathogenic
(Oct 11, 2023)
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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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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004041811.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
Clinical Features:
Breast carcinoma (present)
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Pathogenic
(Jun 07, 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: SCV004044242.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Feb 07, 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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Baylor Genetics
Accession: SCV004217145.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004220710.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The BRIP1 c.2684_2687del (p.Ser895*) variant causes the premature termination of BRIP1 protein synthesis. This variant has been reported in the published literature in affected individuals … (more)
The BRIP1 c.2684_2687del (p.Ser895*) variant causes the premature termination of BRIP1 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 25330149 (2015), 28888541 (2017), 31173646 (2019), 32885271 (2021)) and pancreatic cancer (PMID: 29961768 (2019)). In a large scale breast cancer association study, it was reported in breast cancer cases as well as in a control (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRIP1)). Based on the available information, this variant is classified as pathogenic. (less)
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Likely pathogenic
(Jun 01, 2023)
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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: SCV004009821.7
First in ClinVar: Jul 16, 2023 Last updated: May 12, 2024 |
Comment:
BRIP1: PVS1
Number of individuals with the variant: 1
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Pathogenic
(Jun 11, 2019)
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no assertion criteria provided
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV001451735.1
First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020 |
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Pathogenic
(-)
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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: SCV001554392.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRIP1 p.Ser895* variant was identified in 2 of 26,714 proband chromosomes (frequency: 0.00007) from individuals breast cancer and was present in 1 of 10,484 … (more)
The BRIP1 p.Ser895* variant was identified in 2 of 26,714 proband chromosomes (frequency: 0.00007) from individuals breast cancer and was present in 1 of 10,484 control chromosomes (frequency: 0.00009) from healthy individuals (Cybulski 2015, Easton 2016). The variant was identified in dbSNP (rs760551339) as “with pathogenic allele”, ClinVar (interpreted as "pathogenic" by Invitae and 3 others). The variant was identified in control databases in 4 of 282,712 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,966 chromosomes (freq: 0.00004), European in 3 of 129,072 chromosomes (freq: 0.00002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other, and South Asian populations. The c.2684_2687del variant leads to a premature stop codon at position 895 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRIP1 gene are an established mechanism of disease in Hereditary Breast and Ovarian Cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(Mar 04, 2021)
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no assertion criteria provided
Method: case-control
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Carcinoma of pancreas
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV001593144.1
First in ClinVar: May 14, 2021 Last updated: May 14, 2021 |
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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not provided
(-)
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no classification provided
Method: phenotyping only
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BRIP1-related disorder
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749335.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 10-17-2016 by Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 10-17-2016 by Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Family history of cancer (present)
Indication for testing: Family Testing
Age: 20-29 years
Sex: female
Testing laboratory: Myriad Genetic Laboratories, Inc.,Myriad Genetic Laboratories, Inc.
Date variant was reported to submitter: 2016-10-17
Testing laboratory interpretation: Pathogenic
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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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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing. | Scarpitta R | Breast cancer research and treatment | 2019 | PMID: 31512090 |
The spectrum of mutations predisposing to familial breast cancer in Poland. | Cybulski C | International journal of cancer | 2019 | PMID: 31173646 |
Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes. | Henn J | Hereditary cancer in clinical practice | 2019 | PMID: 30680046 |
Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. | Yurgelun MB | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29961768 |
Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. | Lilyquist J | Gynecologic oncology | 2017 | PMID: 28888541 |
Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. | Cybulski C | Clinical genetics | 2015 | PMID: 25330149 |
Mutations in BRIP1 confer high risk of ovarian cancer. | Rafnar T | Nature genetics | 2011 | PMID: 21964575 |
Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. | Seal S | Nature genetics | 2006 | PMID: 17033622 |
The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. | Levitus M | Nature genetics | 2005 | PMID: 16116423 |
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Text-mined citations for rs760551339 ...
HelpRecord last updated May 12, 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.