ClinVar Genomic variation as it relates to human health
NM_032043.3(BRIP1):c.1899C>G (p.Ile633Met)
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.1899C>G (p.Ile633Met)
Variation ID: 231114 Accession: VCV000231114.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.2 17: 61780297 (GRCh38) [ NCBI UCSC ] 17: 59857658 (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 Feb 19, 2018 Aug 4, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032043.3:c.1899C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_114432.2:p.Ile633Met missense NC_000017.11:g.61780297G>C NC_000017.10:g.59857658G>C NG_007409.2:g.88263C>G LRG_300:g.88263C>G LRG_300t1:c.1899C>G LRG_300p1:p.Ile633Met - Protein change
- I633M
- Other names
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- Canonical SPDI
- NC_000017.11:61780296:G:C
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
5614 | 5671 |
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
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 5, 2023 | RCV000220030.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV000234693.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 19, 2017 | RCV000662814.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 27, 2023 | RCV000990013.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV000781165.10 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2022 | RCV001171799.25 |
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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Uncertain significance
(Feb 01, 2020)
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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: SCV001334659.23
First in ClinVar: Jun 08, 2020 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Jul 05, 2023)
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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: SCV000274862.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.I633M variant (also known as c.1899C>G), located in coding exon 12 of the BRIP1 gene, results from a C to G substitution at nucleotide … (more)
The p.I633M variant (also known as c.1899C>G), located in coding exon 12 of the BRIP1 gene, results from a C to G substitution at nucleotide position 1899. The isoleucine at codon 633 is replaced by methionine, an amino acid with highly similar properties. This variant has been identified in disease cohorts including breast cancer, ovarian cancer, and cutaneous melanoma, as well as unaffected control groups across studies (Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Easton DF et al. J Med Genet, 2016 05;53:298-309; Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in 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. (less)
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Uncertain significance
(Dec 21, 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: SCV002769984.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, ovarian cancer, or melanoma, but also in unaffected controls (Ramus et al., 2015; Easton et al., 2016; Tung et al., 2016; Pritchard et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26315354, 26976419, 29641532, 26921362, 33471991) (less)
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Uncertain significance
(Nov 30, 2020)
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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: SCV000684166.4
First in ClinVar: Feb 19, 2018 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces isoleucine with methionine at codon 633 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces isoleucine with methionine at codon 633 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26976419), in two individuals affected with breast cancer (PMID: 26976419), as well as two unaffected individuals (PMID: 26315354; FLOSSIES, https://whi.color.com/). This variant has not been identified 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. (less)
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Uncertain significance
(Feb 27, 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: SCV004019307.1
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
(Jan 26, 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: SCV000290994.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 633 of the BRIP1 protein (p.Ile633Met). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 633 of the BRIP1 protein (p.Ile633Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRIP1-related conditions (PMID: 26315354, 26921362, 26976419). ClinVar contains an entry for this variant (Variation ID: 231114). 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. (less)
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Uncertain significance
(Jul 31, 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: SCV002551183.5
First in ClinVar: Jul 27, 2022 Last updated: Aug 04, 2024 |
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Uncertain significance
(Oct 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group J
Ovarian cancer
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000785650.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Apr 20, 2019)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919044.2
First in ClinVar: Jun 02, 2019 Last updated: Nov 08, 2019 |
Comment:
Variant summary: BRIP1 c.1899C>G (p.Ile633Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: BRIP1 c.1899C>G (p.Ile633Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 288552 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1899C>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer as well as unaffected controls (Ramus_2016, Tung_2016, Easton_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(May 28, 2019)
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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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Mendelics
Accession: SCV001140776.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
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: SCV001552733.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRIP1 p.Ile633Met variant was identified in 2 of 7448 proband chromosomes (frequency: 0.00023) from individuals or families with hereditary breast and ovarian cancer and … (more)
The BRIP1 p.Ile633Met variant was identified in 2 of 7448 proband chromosomes (frequency: 0.00023) from individuals or families with hereditary breast and ovarian cancer and was present in 1 of 6862 control chromosomes (frequency: 0.0001) from healthy individuals (Ramus 2015, Tung 2016). The variant was also identified in dbSNP (ID: rs28997572) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, Invitae, and Color Genomics), Clinvitae, and Zhejiang University Database. The variant was not identified in the Cosmic or MutDB database. The variant was identified in the Exome Aggregation Consortium (August 8th 2016) control database in 1 of 121336 chromosomes at a frequency of 0.000008 in the following populations: Latino in 1 of 11578 chromosomes (freq: 0.000086), but not observed in the African, East Asian, European (Finnish), European (Non-Finnish), Other, or South Asian populations. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (Feb 27, 2017). The p.Ile633 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, 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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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 |
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 |
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
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 |
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 |
Text-mined citations for rs28997572 ...
HelpRecord last updated Sep 08, 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.