ClinVar Genomic variation as it relates to human health
NM_032043.3(BRIP1):c.1941G>T (p.Trp647Cys)
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.1941G>T (p.Trp647Cys)
Variation ID: 186189 Accession: VCV000186189.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.2 17: 61776557 (GRCh38) [ NCBI UCSC ] 17: 59853918 (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 1, 2024 Nov 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032043.3:c.1941G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_114432.2:p.Trp647Cys missense NC_000017.11:g.61776557C>A NC_000017.10:g.59853918C>A NG_007409.2:g.92003G>T LRG_300:g.92003G>T LRG_300t1:c.1941G>T LRG_300p1:p.Trp647Cys - Protein change
- W647C
- Other names
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- Canonical SPDI
- NC_000017.11:61776556:C: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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 |
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2023 | RCV000165735.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 7, 2016 | RCV000410856.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 7, 2016 | RCV000412383.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2023 | RCV000542964.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 18, 2021 | RCV001778762.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 2, 2022 | RCV001847787.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 2, 2023 | RCV003316047.2 |
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
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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
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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
(Oct 18, 2021)
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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: SCV002014965.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: BRIP1 c.1941G>T (p.Trp647Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: BRIP1 c.1941G>T (p.Trp647Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251268 control chromosomes. c.1941G>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least two individuals affected with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 (Fonfria_2021). One of these individuals reported a triple negative subtype (ER/PR/HER2), while the other reported a triple positive subtype of breast cancer. Furthermore, a different nucleotide substitution, c.1941G>C, that results in an identical amino acid substitution, namely p.Trp647Cys, has been identified along with another FANCJ (BRIP1) allele in an individual affected with Fanconi Anemia (Levitus_2005). Another study reported this specific nucleotide variant in controls but not in breast cancer cases (Weber-Lassalle_2018). Some reports do not specify the exact nucleotide alteration and limit reporting to the affected protein (example, Guo_2016, Bharti_2018 described below). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bharti_2018). The most pronounced variant effect results in <10% of normal helicase activity as evidenced by a decrease in Kcat for ATP hydrolysis in a recombinant FANCJ protein expressing baculovirus system. 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. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Sep 07, 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: SCV000489991.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Sep 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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Ovarian cancer
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489992.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Feb 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Fanconi anemia complementation group J
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786530.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Mar 02, 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: SCV002104363.2
First in ClinVar: Mar 19, 2022 Last updated: Mar 04, 2023 |
Comment:
Observed in individuals with breast cancer (Fonfria 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense … (more)
Observed in individuals with breast cancer (Fonfria 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Another substitution, BRIP1 1941G>C, resulting in the same Trp647Cys missense variant has been observed in at least one individual with breast cancer and has been co-observed with a second BRIP1 variant, phase unknown, in an individual with Fanconi anemia (Levitus 2005, Lajus 2015). Furthermore BRIP1 1941G>C (Trp647Cys) has been associated with absent helicase activity and reduced ATP hydrolysis (Bharti 2018).; This variant is associated with the following publications: (PMID: 16116423, 29368626, 23276657, 17145708, 29788478, 25981591, 34204722) (less)
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Uncertain significance
(Feb 28, 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: SCV004019385.1
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
(Sep 02, 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: SCV004214774.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Apr 11, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684170.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces tryptophan with cysteine at codon 647 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces tryptophan with cysteine at codon 647 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant protein displays reduced helicase activity in an in vitro assay (PMID: 29788478). While this variant has not been reported in individuals affected with BRIP1-associated diseases in the literature, a different variant (c.1941G>C) resulting in the same amino acid change has been reported in individuals affected with Fanconi anemia and breast cancer (PMID: 16116423, 25981591). 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
(Nov 01, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000633583.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 647 of the BRIP1 … (more)
This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 647 of the BRIP1 protein (p.Trp647Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25981591). ClinVar contains an entry for this variant (Variation ID: 186189). 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%. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 29788478). 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
(Jun 06, 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: SCV000216476.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.W647C variant (also known as c.1941G>T), located in coding exon 13 of the BRIP1 gene, results from a G to T substitution at nucleotide … (more)
The p.W647C variant (also known as c.1941G>T), located in coding exon 13 of the BRIP1 gene, results from a G to T substitution at nucleotide position 1941. The tryptophan at codon 647 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was not observed in 706 cases with ovarian cancer or 6341 cases with breast cancer and was observed in 1/36687 healthy controls (Weber-Lassalle N et al. Breast Cancer Res., 2018 01;20:7). Another alteration that results in the same amino acid change (c.1941G>C) has been identified in conjunction with a BRIP1 mutation in an individual diagnosed with Fanconi Anemia complementation group J (FA-J); Western blot demonstrated attenuated protein expression in this individual (Levitus M, Nat. Genet. 2005 Sep; 37(9):934-5). Functional assays indicate this alteration inactivates the helicase activity of the protein, and severely compromises its ability to hydrolyze ATP (Bharti SK et al. Nucleic Acids Res., 2018 Jul;46:6238-6256). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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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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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Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families. | Fonfria M | Journal of personalized medicine | 2021 | PMID: 34204722 |
A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair. | Bharti SK | Nucleic acids research | 2018 | PMID: 29788478 |
BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. | Weber-Lassalle N | Breast cancer research : BCR | 2018 | PMID: 29368626 |
Mutational analysis of FANCJ helicase. | Guo M | Methods (San Diego, Calif.) | 2016 | PMID: 27107905 |
CDH1 germ-line missense mutation identified by multigene sequencing in a family with no history of diffuse gastric cancer. | Lajus TB | Gene | 2015 | PMID: 25981591 |
The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. | Levitus M | Nature genetics | 2005 | PMID: 16116423 |
Text-mined citations for rs786202760 ...
HelpRecord last updated Sep 29, 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.